New therapies

Laser therapy in acute stroke treatment

Samuel Yip and Justin Zivin

confirmatory phase III trial, was neutral (8, 9). The strategy of
Abstract Recent development of near infrared light therapy
neuroprotection is now queried, because of the failure to
(NILT) as an acute stroke treatment is promising. In various
demonstrate the principle of neuroprotective therapy in
preclinical animal stroke models, NILT has been shown to be
acute stroke patients. As a new approach is clearly needed,
effective in improving long-term stroke outcome. More im-
various neuroprotective tools including clot extractors or
portantly, NILT has a long postischemic therapeutic window
hypothermia are being developed. Recently, promising data
that has not been previously observed in other treatment
from a phase II trial of phototherapy in acute stroke patients
modalities. The preliminary efficacy and safety of NILT in acute
was reported (11). This review will focus on the recent
stroke patients were demonstrated in the recently published
literature on near-infrared light therapy (NILT) in acute stroke
phase II NeuroThera Effectiveness and Safety Trial (NEST-1). If
treatment.
confirmed by the NEST-II trial, NILT will revolutionize acute
stroke management as ut has a long time window (possible 24
hr) for therapy. Moreover, understanding the mechanisms of
Infrared irradiation as a therapeutic agent
action of NILTwill provide a new therapeutic target for future
drug or device development. The physiological function of light has been studied extensively
Key words: acute stroke therapy, ischemic stroke, treatment, in the photoreceptors of the retina, in the metabolism of
near infrared light therapy, laser therapy, clinical trial Vitamin D as well as the process of photosynthesis in plants.
These physiological functions are based on the principle of
photobiostimulation in which various parts of the electro-
The only proven effective acute stroke treatment is intravenous
magnetic spectrum are capable of altering biochemical reac-
tissue plasminogen activator (t-PA) given within the first 3 h of
tions (12). Although some of the therapeutic outcomes of laser
stroke onset (1). Owing to the short onset to treatment time, t-
therapy are due to its photothermal effect, NILT typically does
PA is underutilized (2). Numerous efforts to identify other
not cause a significant increase in temperature. It is believed
acute stroke therapy, mostly using neuroprotectants, have not
that photobiostimulation is the underlying mechanism of the
been met with success (3). The most recent and disastrous of
therapeutic action of NILT observed in variety of diseases
these efforts in neuroprotective therapy concept, was the
including, carpel tunnel syndrome (CTS), rheumatoid arthri-
development of NXY-059 (4, 5).
tis, osteoarthritis, and wound healing.
Based on numerous preclinical data, NXY-059 was viewed
In CTS, it has been proposed that the decrease in symptoms
as one of the most promising compound for acute stroke
is attributed to the anti-inflammatory and analgesic effects of
therapy (6, 7). Its efficacy as a neuroprotective agent in acute
NILT (13–15). A limited number of controlled clinical studies
stroke was investigated in the recently published SAINT-I and
have reported the efficacy of NILT in CTS but these results have
SAINT-II trials. These trials were designed specifically to fulfill
been controversial (Table 1) (16–18). Some CTS clinical trial
the criteria set forth by the Stroke Therapy Academic Industry
outcomes are limited due to the small number of patients
Roundtable committee with regards to translational research
enrolled, therefore, the positive findings may be random (19,
from animal study to large-scale human phase III stroke trials
20). More importantly, among the different trials there was not
(8–10). The SAINT-I study showed a small but statistically
a standardized laser setting [wavelength, power density (PD),
significant benefit of NXY-059 on the primary outcome of shift
or treatment duration] for the NILT, making direct compar-
in modified Rankin Scale (mRS); however, SAINT-II, a larger
isons among trials impossible (19). Similar issues also plagued
the literature of NILT in osteoarthritis, rheumatoid arthritis,
Correspondence: Dr Justin Zivin, Department of Neuroscience,
and wound healing as have been discussed in recent reviews
University of California, San Diego, 9500 Gilman Drive, La Jolla, CA (21–23). The therapeutic effects of NILT in human diseases
92093-0624, USA. e-mail: [email protected] remain questionable.

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88 Journal compilation & 2008 International Journal of Stroke Vol 3, May 2008, 88–91
 S. Yip & J. Zivin New therapies
Table 1 Summary of methods and results of published controlled trials using NILT to treat CTS

Author N Trial design Laser settings Outcome

2
Naeser et al. (2002) 11 R, DB, SC 632
8 nm, CW, 32
3 J/cm at wrist1addition points in Benefit
forearm, shoulder, cervical neck at 904 nm, pulse mode,
o1–2 J/cm2
Irvine et al. (2004) 15 R, DB, SC 860 nm, CW, 6 J/cm2 at wrist No benefit
Evcik et al. (2006) 81 R, DB, SC 830 nm, pulsed, 8
9 J/cm2 at wrist No benefit

R, randomized; DB, double blind; SC, sham controlled; NILT, near-infrared light therapy; CTS, carpel tunnel syndrome; CW, continuous wave.

Mechanism of actions experiments are analyzed by a quantal-dose response techni-

que measuring the amount of microclots that produce neuro-
One putative mechanism of action of laser therapy is thought
logic dysfunction in 50% of a group of animals (P50) (36). In
to be related to increase in ATP production by stimulating the
this model, laser therapy [wavelength (l) 5 808 nm in con-
cytochrome c oxidase (24, 25). The copper centers within the
tinuous wave (CW) mode, PD 5 25 mW/cm2, duration 5 10 -
cytochrome c oxidase act as a photo acceptor, and absorption
min] initiated up to 6 h after embolization was shown to
of the near infrared radiation by this enzyme results in
significantly increase the P50 value (2
9870
65 mg in NILT
acceleration of electron transfer and increase in ATP produc-
treated group vs. 0
9770
19 mg in control group)
tion. ATP level is increased significantly in laser-treated heart
and to improve behavioral rating scores when measured at
and skeletal muscles (24, 25). NILT at 808–810 nm can
24 h posttreatment (31, 37). This effect is durable as demon-
penetrate the brain and lead to enhanced production of ATP
strated when measured up to 21 days after stroke onset.
in rat cerebral cortex (26). In cultured human neural progeni-
Importantly, the 6-h treatment window of NILT is the longest
tor cells, laser treatment results in doubling of ATP content
effective onset to treatment time that has been shown in this
(27). In addition to enhanced ATP production, other mechan-
preclinical model compared with other previously investigated
isms of action have also been implicated. In ischemic models of
treatments (34, 35). This finding suggests that NILT may
the heart and skeletal muscles, NILT increases heat shock
induce a rapid response element in the brain following
proteins and preserves mitochondrial function (25). In a
embolization and result in early neurobehavioral improve-
model of transient cerebral ischemia, NILT inhibited nitric
ment as well as some slower response that produces recovery of
oxide synthase activity, and upregulated expression of TGF b-1
function (31, 37).
(28). Based on these findings, it is thought that NILT may have
Others have found similar favorable effects of NILT in the rat
multiple mechanisms of action and could be beneficial in acute
filament induced permanent middle cerebral artery occlusion
ischemic stroke (25).
(MCAO) stroke model. In this MCAO model, Oron et al.
In the field of bone remodeling, infrared laser therapy has
demonstrated that laser therapy (l 5 808 nm in CW mode,
been shown to increase osteoblastic proliferation, collagen
PD 5 7
5 W/cm2, duration 5 2 min) when applied at 24 h
deposition, and bone neo-formation when compared with
poststroke, produced a statistically significant 47% improve-
nonirradiated bone (29). In wound healing studies, NILT
ment of neurological severity score as compared with control
increased the proliferation of various skin cell types, including
when measured 14 days poststroke (30). This improvement
fibroblasts, endothelial cells, and keratinocytes in cell culture
was durable up to 21 days. Additional data published by the
models (23). Similarly, findings of increased neurogenesis in
manufacturer of the low energy laser device, Photothera Inc.
the subventricular zone (SVZ) were reported in an ischemic
(Carlsbad, CA) also supports this finding (38). De Taboda et al.
stroke animal model treated with NILT (30). Whether these
in the same rat MCAO model used by Oron, demonstrated that
increase in cell proliferation in different tissue types have a
animals treated with NILT (l 5 808 nm in CW mode,
common underlying mechanism still needs to be further
PD 5 7
5 mW/cm2, duration 5 2 min), showed a significant
identified.
improvement in neurological score at 14 days (38% vs. 24%, in
treated vs. control groups, respectively) and continue to
improve at 28 days poststroke (63% vs. 32%, in treated vs.
In vivo animal model
control groups, respectively).
Lapchak et al. used the rabbit small clot embolic stroke model There are a few of the findings in these animal models that
(RSCEM), and were the first group to demonstrate the suggest recanalization and neuroprotection may not be the
beneficial effects of NILT in acute ischemic stroke (31). The primary mechanism of action of NILT. First, the treatment was
RSCEM was the principal model used to show improvement effective up to 6 h in the RSCEM and up to 24 h in the rat
without excessive hemorrhage in the preclinical studies of t-PA MCAO model (30, 31, 37, 38). The onset to treatment time is
(32, 33); and has been used to study many other treatment much longer than any therapy tested in the past and argues
modalities in acute stroke (34, 35). The results from these against a recanalization/hemodynamic mechanism as a major

& 2008 The Authors.

Journal compilation & 2008 International Journal of Stroke Vol 3, May 2008, 88–91 89
 New therapies S. Yip & J. Zivin

contribution. One may argue that augmentation of collateral with a range of 0–42; with a maximum achievable score of 40
flow may help in preserving penumbra and results in an points in coma patients) at 90 days. bNIH measured at 90 days
improved outcome; however, this seems unlikely given that showed a statistically significant benefit in the treatment group
the final infarct volume is not statistically different between the (70%) vs. control group (51%). The secondary outcome
treated and placebo group in the rat model (30). measures of mRS, binary mRS, and Barthel Index, which are
Aside from neuroprotection and recanalization, other ways more reflective of the overall function of patients, also showed
to achieve improved outcome is to enhance recovery using significant differences between the laser treated vs. control
neurogenesis or CNS plasticity. Recent evidence in both animal sham group in favor of the treatment arm. The mortality rates
and human data suggests that after generalized or focal and serious adverse events (SAEs) rates did not differ sig-
ischemia there is an increase in neurogenesis in the SVZ of nificantly between the active treatment and control groups
the lateral ventricle and the subgranular zone of the hippo- (8
9% and 25
3% for active vs. 9
5% and 36
6% for control,
campal dentate gyrus (39). These neurons may migrate to a respectively, for mortality and SAEs).
perilesional area and play a role in the postischemic recovery Because of the promising results of the NEST-1 trial, a
process (39). The idea of improved neurogenesis as an under- confirmatory trial, NEST-2, is currently underway. NEST-2 is a
lying mechanism of NILT was supported by the findings that phase III, prospective, double-blind, randomized, sham-con-
there is a twofold, statistically significant increase in the Brd/ trolled, parallel group, multi-center trial. Patients with stroke
TUJ1 immunoreactivity in the laser-treated rats as compared onset to treatment time that is o24 h can be enrolled into the
with the control sample (30). The percentages of DCX trial. Subjects are randomized to NeuroThera-treated group
immunoreactivity of SVZ area was significantly elevated by vs. sham control group in a 1 : 1 ratio. Subjects will be followed
75% in the laser-treated group relative to control (30). This for 90 days poststroke onset. The primary outcome measure is
finding further suggests that these SVZ cells are capable of the binary endpoint that defines success as a mRS score of 0–2
migration to other areas of the brain. and failure as a mRS score of 3–6 at 90 days. The secondary
Important differences noted between the data from the outcome is the change in NIHSS score from baseline to 90 days
RSCESM vs. the MCAO model were raised by recent findings analyzed across the full range of scores on the NIHSS. The aim
of Lapchak et al. (37). In the rat MCAO model, NILT at 4 h is to enroll approximately 660 patients and recruitment is
poststroke induction did not show a significant effect on expected to be completed by March 2008 (11). If it is successful,
outcome; whereas, in the RSCEM, improved functional out- the results will be revolutionary for stroke therapy, particularly
come it was demonstrated when NILTwas given 1 h poststroke because it permits such a long time window for therapy.
(30, 31, 37). In the rat MCAO model, there is a delayed effect of Because the mechanisms of action of NILT and t-PA are likely
NILT that is only measurable 14 days poststroke while in the different, their interaction will need to be further assessed.
RSCEM, a significantly improved outcome was measurable at
24–48 h posttreatment (30, 31, 37). It is not clear whether the
different results can be explained by the varying animal models Conclusion
or the variables of the NILT settings used in each study. NILT is promising for stroke therapy. Preclinical findings and a
phase II clinical trial provide encouraging results. A confirma-
Human study tory phase III trial (NEST-2) is currently in progress. Because
the onset treatment time is longer than that of t-PA, it will be
Based on the beneficial effects of NILT demonstrated in the able to capture a larger portion of the stroke victim population
preclinical animal stroke models, the NeuroThera Effective- who present later than 3 h postsymptom onset. Combination
ness and Safety Trial-1 (NEST-1) was conducted to evaluate the with t-PA may be useful because the mechanisms of action of
safety and preliminary effectiveness of NILT in ischemic stroke NILT and thrombolysis are almost certainly different. The
patients using the NeuroThera, a laser device produced by optimal laser settings to produce the most therapeutic benefit
Photothera Inc. (11). NEST-1 was a prospective, intention-to- of NILT has not been studied systematically; therefore, the
treat, multicenter, double-blind, sham-controlled trial in issues of dosage, area of irradiation, application time, and
which transcranial low energy (10 mW/cm2 in CW mode) duration of a course of treatment needs to be further evaluated.
infrared laser with a wavelength of 808 nm was applied at 20 Finally, the mechanism of action of NILT in acute stroke will
predetermined locations on the scalp for 2 min of irradiation at need to be further studied as this may provide us with new
each site within 24 h from stroke onset, regardless of the targets of intervention by other means.
location of the vascular occlusion. One hundred and twenty
patients were enrolled with 79 and 41 patients in the active and
sham control groups, respectively. The mean time to treat from
onset was 16 h. The primary outcome measure is binary NIH References
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