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New therapies

Laser therapy in acute stroke treatment

Samuel Yip and Justin Zivin

Abstract Recent development of near infrared light therapy

(NILT) as an acute stroke treatment is promising. In various

preclinical animal stroke models, NILT has been shown to be

effective in improving long-term stroke outcome. More im-

portantly, NILT has a long postischemic therapeutic window

that has not been previously observed in other treatment

modalities. Thepreliminaryefficacy andsafetyof NILT in acute

stroke patients were demonstrated in the recently published

phase II NeuroThera Effectiveness and Safety Trial (NEST-1). If

confirmed by the NEST-II trial, NILT will revolutionize acute

stroke managementas uthas a long time window(possible24

hr) for therapy. Moreover, understanding the mechanisms of

actionof NILTwill provide a new therapeutic target for future

drug or device development.

Key words: acute stroke therapy, ischemic stroke, treatment,

near infrared light therapy, laser therapy, clinical trial

The only proven effective acute stroke treatment is intravenous

tissueplasminogen activator (t-PA) given withinthe first 3 h of

stroke onset (1). Owing to the short onset to treatment time, t-

PA is underutilized (2). Numerous efforts to identify other

acute stroke therapy, mostly using neuroprotectants, have not

been met with success (3). The most recent and disastrous of

these efforts in neuroprotective therapy concept, was the

development of NXY-059 (4, 5).

Based on numerous preclinical data, NXY-059 was viewed

as one of the most promising compound for acute stroke

therapy (6, 7). Its efficacy as a neuroprotective agent in acute

stroke was investigated in the recently published SAINT-I and

SAINT-II trials. These trials were designed specifically to fulfillthe criteria set forth by the Stroke Therapy Academic Industry

Roundtable committee with regards to translational research

from animal study to large-scale human phase III stroke trials

(810). The SAINT-I study showed a small but statistically

significant benefit of NXY-059 on the primary outcome of shift

in modified Rankin Scale (mRS); however, SAINT-II, a larger

confirmatory phase III trial, was neutral (8, 9). The strategy of

neuroprotection is now queried, because of the failure to

demonstrate the principle of neuroprotective therapy in

acute stroke patients. As a new approach is clearly needed,

various neuroprotective tools including clot extractors or

hypothermia are being developed. Recently, promising datafrom a phase II trial of phototherapy in acute stroke patients

was reported (11). This review will focus on the recent

literature on near-infrared light therapy (NILT) in acute stroke

treatment.

Infrared irradiation as a therapeutic agent

The physiological functionof lighthas been studied extensively

in the photoreceptors of the retina, in the metabolism of

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-magnetic spectrum are capable of altering biochemical reac-

tions (12). Although some of thetherapeutic outcomesof laser

therapy are due to its photothermal effect, NILT typically does

not cause a significant increase in temperature. It is believed

that photobiostimulation is the underlying mechanism of the

therapeutic action of NILT observed in variety of diseases

including, carpel tunnel syndrome (CTS), rheumatoid arthri-

tis, osteoarthritis, and wound healing.

In CTS, it has been proposed that the decrease in symptoms

is attributed to the anti-inflammatory and analgesic effects of

NILT (1315). A limited number of controlled clinical studies

have reported theefficacyof NILT in CTSbut these results have

been controversial (Table 1) (1618). Some CTS clinical trial

outcomes are limited due to the small number of patients

enrolled, therefore, the positive findings may be random (19,

20). More importantly, among the different trialstherewas not

a standardized laser setting [wavelength, power density (PD),

or treatment duration] for the NILT, making direct compar-

isons among trials impossible (19). Similar issues also plagued

the literature of NILT in osteoarthritis, rheumatoid arthritis,

and wound healing as have been discussed in recent reviews

(2123). The therapeutic effects of NILT in human diseases

remain questionable.

Correspondence: Dr Justin Zivin, Department of Neuroscience,

University of California, San Diego, 9500 Gilman Drive, La Jolla, CA

92093-0624, USA. e-mail: jzivin@ucsd.edu

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Mechanism of actions

One putative mechanism of action of laser therapy is thought

to be related to increase in ATP production by stimulating the

cytochrome coxidase (24, 25). The copper centers within the

cytochrome coxidase act as a photo acceptor, and absorption

of the near infrared radiation by this enzyme results in

acceleration of electron transfer and increase in ATP produc-

tion. ATP level is increased significantly in laser-treated heartand skeletal muscles (24, 25). NILT at 808810 nm can

penetrate the brain and lead to enhanced production of ATP

in rat cerebral cortex (26). In cultured human neural progeni-

tor cells, laser treatment results in doubling of ATP content

(27). In addition to enhanced ATP production, other mechan-

isms of actionhavealso been implicated. In ischemic modelsof

the heart and skeletal muscles, NILT increases heat shock

proteins and preserves mitochondrial function (25). In a

model of transient cerebral ischemia, NILT inhibited nitric

oxide synthase activity, and upregulated expression of TGFb-1

(28). Based on these findings, it is thought that NILT may have

multiplemechanisms of actionand couldbe beneficial in acute

ischemic stroke (25).In the field of bone remodeling, infrared laser therapy has

been shown to increase osteoblastic proliferation, collagen

deposition, and bone neo-formation when compared with

nonirradiated bone (29). In wound healing studies, NILT

increased the proliferation of various skin cell types, including

fibroblasts, endothelial cells, and keratinocytes in cell culture

models (23). Similarly, findings of increased neurogenesis in

the subventricular zone (SVZ) were reported in an ischemic

stroke animal model treated with NILT (30). Whether these

increase in cell proliferation in different tissue types have a

common underlying mechanism still needs to be further

identified.

In vivo animal model

Lapchaket al. used the rabbit small clot embolic stroke model

(RSCEM), and were the first group to demonstrate the

beneficial effects of NILT in acute ischemic stroke (31). The

RSCEM was the principal model used to show improvement

without excessive hemorrhage in the preclinical studies of t-PA

(32, 33); and has been used to study many other treatment

modalities in acute stroke (34, 35). The results from these

experiments are analyzed by a quantal-dose response techni-

que measuring the amount of microclots that produce neuro-

logic dysfunction in 50% of a group of animals (P50) (36). In

this model, laser therapy [wavelength (l)5 808 nm in con-

tinuous wave (CW) mode, PD5 25 mW/cm2, duration510 -

min] initiated up to 6 h after embolization was shown to

significantly increase the P50 value (2987065 mg in NILT

treated group vs. 0977019mg in control group)

and to improve behavioral rating scores when measured at24 h posttreatment (31, 37). This effect is durable as demon-

strated when measured up to 21 days after stroke onset.

Importantly, the 6-h treatment window of NILT is the longest

effective onset to treatment time that has been shown in this

preclinical model compared with other previously investigated

treatments (34, 35). This finding suggests that NILT may

induce a rapid response element in the brain following

embolization and result in early neurobehavioral improve-

ment as well as some slower responsethat producesrecovery of

function (31, 37).

Othershavefoundsimilarfavorable effects of NILT in the rat

filament induced permanent middle cerebral artery occlusion(MCAO) stroke model. In this MCAO model, Oron et al.

demonstrated that laser therapy (l5 808 nm in CW mode,

PD5 75 W/cm2, duration5 2 min) when applied at 24 h

poststroke, produced a statistically significant 47% improve-

ment of neurological severity score as compared with control

when measured 14 days poststroke (30). This improvement

was durable up to 21 days. Additional data published by the

manufacturer of the low energy laser device, Photothera Inc.

(Carlsbad, CA) alsosupportsthis finding (38).De Taboda etal.

in the same ratMCAO modelusedby Oron, demonstratedthat

animals treated with NILT (l5808 nm in CW mode,

PD5 75 mW/cm2, duration5 2 min), showed a significant

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.

control groups, respectively).

There are a few of the findings in these animal models that

suggest recanalization and neuroprotection may not be the

primary mechanism of action of NILT. First, the treatment was

effective up to 6 h in the RSCEM and up to 24 h in the rat

MCAO model (30, 31, 37, 38). The onset to treatment time is

much longer than any therapy tested in the past and argues

against a recanalization/hemodynamic mechanism as a major

Table 1 Summary of methods and results of published controlled trials using NILT to treat CTS

Author N Trial design Laser settings Outcome

Naeser et al. (2002) 11 R, DB, SC 6328 nm, CW, 323J/cm2 at wrist1addition points in

forearm, shoulder, cervical neck at 904 nm, pulse mode,

o12J/cm2

Benefit

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, 89J/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.

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contribution. One may argue that augmentation of collateral

flow may help in preserving penumbra and results in an

improved outcome; however, this seems unlikely given that

the final infarct volume is not statisticallydifferent between the

treated and placebo group in the rat model (30).

Aside from neuroprotection and recanalization, other ways

to achieve improved outcome is to enhance recovery usingneurogenesis or CNSplasticity. Recent evidence in bothanimal

and human data suggests that after generalized or focal

ischemia there is an increase in neurogenesis in the SVZ of

the lateral ventricle and the subgranular zone of the hippo-

campal dentate gyrus (39). These neurons may migrate to a

perilesional area and play a role in the postischemic recovery

process (39). The idea of improved neurogenesis as an under-

lying mechanism of NILT was supported by the findings that

there is a twofold, statistically significant increase in the Brd/

TUJ1 immunoreactivity in the laser-treated rats as compared

with the control sample (30). The percentages of DCX

immunoreactivity of SVZ area was significantly elevated by

75% in the laser-treated group relative to control (30). Thisfinding further suggests that these SVZ cells are capable of

migration to other areas of the brain.

Important differences noted between the data from the

RSCESM vs. the MCAO model were raised by recent findings

of Lapchak et al. (37). In the rat MCAO model, NILT at 4 h

poststroke induction did not show a significant effect on

outcome; whereas, in the RSCEM, improved functional out-

come it was demonstrated when NILTwas given 1 h poststroke

(30, 31, 37). In the rat MCAO model, there isa delayed effect of

NILT that is only measurable 14 days poststroke while in the

RSCEM, a significantly improved outcome was measurable at

2448 h posttreatment (30, 31, 37). It is not clear whether thedifferent results can be explainedby the varyinganimal models

or the variables of the NILT settings used in each study.

Human study

Based on the beneficial effects of NILT demonstrated in the

preclinical animal stroke models, the NeuroThera Effective-

nessand Safety Trial-1 (NEST-1) was conducted to evaluate the

safety and preliminary effectiveness of NILT in ischemic stroke

patients using the NeuroThera, a laser device produced by

Photothera Inc. (11). NEST-1 was a prospective, intention-to-

treat, multicenter, double-blind, sham-controlled trial in

which transcranial low energy (10 mW/cm2 in CW mode)

infrared laser with a wavelength of 808 nm was applied at 20

predetermined locations on the scalpfor 2 minof irradiation at

each site within 24 h from stroke onset, regardless of the

location of the vascular occlusion. One hundred and twenty

patients were enrolled with 79 and41 patients in the active and

shamcontrolgroups, respectively. The meantime to treat from

onset was 16 h. The primary outcome measure is binary NIH

(bNIH) score. A positive bNIH score was defined as a final

score of 01 or a 9-point decrease in the NIH Stroke Scale

(NIHSS a simplified neurological examination rating score

with a range of 042; with a maximum achievable score of 40

points in coma patients) at 90 days. bNIH measured at 90 days

showed a statistically significant benefit in the treatment group

(70%) vs. control group (51%). The secondary outcome

measures of mRS, binary mRS, and Barthel Index, which are

more reflective of the overall function of patients, also showed

significant differences between the laser treated vs. controlsham group in favor of the treatment arm. The mortality rates

and serious adverse events (SAEs) rates did not differ sig-

nificantly between the active treatment and control groups

(89% and 253% for active vs. 95% and 366% for control,

respectively, for mortality and SAEs).

Because of the promising results of the NEST-1 trial, a

confirmatory trial, NEST-2, is currentlyunderway. NEST-2 is a

phase III, prospective, double-blind, randomized, sham-con-

trolled, parallel group, multi-center trial. Patients with stroke

onset to treatment time that iso24 h can be enrolled into the

trial. Subjects are randomized to NeuroThera-treated group

vs. sham control group in a 1 : 1 ratio. Subjects will be followed

for 90 days poststroke onset. The primary outcome measure isthe binary endpoint that defines success as a mRS score of 02

and failure as a mRS score of 36 at 90 days. The secondary

outcome is thechange in NIHSS score from baselineto 90 days

analyzed across the full range of scores on the NIHSS. The aim

is to enroll approximately 660 patients and recruitment is

expected tobe completed by March2008 (11). If it is successful,

the results will be revolutionary for stroke therapy, particularly

because it permits such a long time window for therapy.

Because the mechanisms of action of NILT and t-PA are likely

different, their interaction will need to be further assessed.

Conclusion

NILT is promising for stroke therapy. Preclinical findings and a

phase II clinical trial provide encouraging results. A confirma-

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

able to capture a larger portion of the stroke victimpopulation

who present later than 3 h postsymptom onset. Combination

with t-PA may be useful because the mechanisms of action of

NILT and thrombolysis are almost certainly different. The

optimal laser settings to produce the most therapeutic benefit

of NILT has not been studied systematically; therefore, the

issues of dosage, area of irradiation, application time, andduration of a courseof treatmentneedsto be furtherevaluated.

Finally, the mechanism of action of NILT in acute stroke will

need to be further studied as this may provide us with new

targets of intervention by other means.

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