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Transcranial laser therapy for acute ischemic stroke

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Versión publicada: 16 noviembre 2016 Historial de versiones

https://doi.org/10.1002/14651858.CD012426
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and safety of transcranial laser therapy (TLT) for improving functional outcomes after acute ischemic stroke.

Background

Description of the condition

Stroke is the second most common cause of death worldwide, and a major global cause of disability (Liu 2007). Approximately 80% of all strokes are ischemic (Donnan 2008). At present, the only effective and proven treatment for acute ischemic stroke is intravenous thrombolysis with tissue plasminogen activator (t‐PA) when given within 4.5 hours after stroke onset (Hacke 2008). In addition to intravenous thrombolysis, recently thrombectomy has also become a proven effective treatment for acute ischemic stroke within six hours after stroke onset (Powers 2015). Although the rate at which intravenous thrombolysis and thrombectomy is given has increased, considering the brief window of time for administration and the risk of bleeding, only a few people with acute ischemic stroke can benefit from these treatments (Hanley 2005; Jin 2012). Newer and safer treatments, especially with longer treatment windows, are urgently needed to benefit more people with acute ischemic stroke. In addition, some other treatments may be given along with intravenous thrombolysis and thrombectomy to help treat the residual problems suffered by people with stroke, such as paralysis, language problems, and visual neglect.

Description of the intervention

Transcranial laser therapy (TLT) is a non‐invasive brain stimulation technology using near‐infrared laser energy transmitted through the scalp and skull to modulate biochemical changes within neural cells (Stemer 2010). The energy in the near‐infrared spectrum at a wavelength of 808 nm is non‐ionizing, invisible to the naked eye, and is not associated with the risks of ionizing radiation (Yip 2008). It can promote energy production (Streeter 2004), neuroprotection (Leung 2002), neurogenesis and neuroplasticity (Oron 2006; Rochkind 2009; Xuan 2014; Xuan 2015), and can eventually improve functional outcomes (Leung 2002).

How the intervention might work

Multiple mechanisms are believed to be involved in TLT photobiostimulation in people with ischemic stroke (Yip 2008), including the promotion of enzymatic activity and improving adenosine triphosphate (ATP) formation through near‐infrared radiation absorbed by mitochondrial chromophores, both of which may inhibit apoptosis, enhance neurorecovery, and contribute to function restoration (Conlan 1996; Mochizuki‐Oda 2002; Streeter 2004). Taken together, TLT may promote functional and behavioral recovery through energy metabolism and by enhancing cerebral blood flow (Nawashiro 2012; Schiffer 2009). Given the existing evidence, the mechanism of TLT in stroke seems to be multifactorial.

Why it is important to do this review

The application of TLT had been explored in the treatment of other conditions, including carpal tunnel syndrome (Evcik 2007; Irvine 2004; Naeser 2002; Naeser 2006), rheumatoid arthritis (Brosseau 2005), osteoarthritis (Brosseau 2004), and wound healing (Posten 2005). In addition, preclinical research with TLT used in different stroke models has reported encouraging and positive results that show the possibility of TLT application in stroke to improve functional outcomes in human beings (Detaboada 2006; Lapchak 2004; Oron 2006). There have also been a few published clinical trials measuring the effectiveness and safety of TLT in people with acute ischemic stroke but the results are controversial (Hacke 2014; Huisa 2013; Lampl 2007; Zivin 2009). The purpose of this review is to systematically evaluate all the randomized controlled trials (RCTs) of TLT on functional improvement in people with acute ischemic stroke to provide the best available evidence.

Objectives

To assess the efficacy and safety of transcranial laser therapy (TLT) for improving functional outcomes after acute ischemic stroke.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs comparing the efficacy and safety of transcranial laser therapy (TLT) with sham treatment, other conventional treatment or no therapy in people with acute ischemic stroke.

Types of participants

We will include studies with participants of any age and either sex after acute ischemic stroke, regardless of stroke severity on admission. Stroke should be diagnosed according to World Health Organization criteria (Sacco 2013; Stroke 1989), excluding intracerebral hemorrhage, subarachnoid hemorrhage or stroke mimics by computerized tomography (CT) or magnetic resonance imaging (MRI) scan.

Types of interventions

We will include trials evaluating the efficacy and safety of TLT in people with acute ischemic stroke. The control interventions are sham treatment, other conventional treatment or no therapy.

We will compare:

  • TLT only compared with sham treatment;

  • TLT only compared with no therapy;

  • TLT add‐on baseline treatment compared with sham treatment add‐on baseline treatment;

  • TLT add‐on baseline treatment compared with baseline treatment alone.

Types of outcome measures

We will evaluate outcomes at the end of the scheduled treatment period and the scheduled follow‐up period.

Primary outcomes

Assessment of functional outcome, as measured by scales such as the modified Rankin Scale (mRS) and Glasgow Outcome Scale, at discharge and follow‐up. The mRS measures the level of a person's disability in terms of dependency (modified Rankin scale 3 to 6) (Van Swieten 1988).

Secondary outcomes

  • Assessment of stroke severity using the National Institutes of Health Stroke Scale (NIHSS) score at discharge and follow‐up.

  • Death rate at discharge and follow‐up.

  • Adverse outcome (such as seizure, headache, dizziness, etc.) during the treatment period and scheduled follow‐up.

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We will search for trials in all languages and arrange for the translation of relevant articles where necessary.

Electronic searches

We will search the Cochrane Stroke Group trials register and the following electronic databases.

We will also search the following ongoing trials registers.

We developed the MEDLINE search strategy with the help of the Cochrane Stroke Group Information Specialist and will adapt it for the other databases (Appendix 1).

Searching other resources

In order to identify further published, unpublished and ongoing studies, we will search databases of conference abstracts and all reference lists of articles retrieved in full. When necessary we will also attempt to contact the relevant study authors to obtain further data.

Data collection and analysis

Selection of studies

Two review authors (JL, SW) will independently screen titles and abstracts of the references retrieved from our searching activities and exclude those that are obviously irrelevant. We will obtain the full‐text articles for the remaining references and will independently scrutinize them to identify studies for inclusion; we will record the reasons for excluding ineligible studies. We will resolve any disagreements through discussion or, if required, we will consult a third review author (ML). We will collate multiple reports of the same study so that each study, not each reference, is the unit of interest in the review. We will record the selection process and provide a PRISMA flow diagram.

Data extraction and management

Two review authors (JL, SH) will independently extract data from the included studies using a data extraction form. We will extract data in relation to participant characteristics, methods, interventions, and outcomes. We will resolve disagreements by discussion; when necessary we will consult a third review author (ML). For dichotomous outcomes, we will extract the number of participants experiencing the event and the total number of participants in each arm of the trial. For continuous outcomes, we will extract the mean value and standard deviation for the changes in each arm of the trial along with the total number in each group. Wherever possible, we will use outcomes from the intention‐to‐treat (ITT) population and, if not possible, we will extract per protocol outcomes.

Assessment of risk of bias in included studies

Two review authors (JL, SW) will independently assess risk of bias for each study using Cochrane's 'Risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (ML). We will evaluate the risk of bias according to the following aspects.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias (such as bias of recruiting subjects, and publication bias).

We will categorize the risk of bias for each domain above as high, low or unclear and provide information from the study report together with a justification for our judgment in the 'Risk of bias' tables.

Measures of treatment effect

For dichotomous outcomes, we will express results as risk ratios (RRs) with 95% confidence intervals (CI). For continuous outcomes, we will present results as mean differences (MDs) if the same scale for each trial is available; or standardized mean differences (SMD) if different scales were used. Also for continuous outcomes, we intend to compare the change between groups after randomization and at the end of the scheduled follow‐up period.

Unit of analysis issues

For each included study, we will review the level at which randomization occurs and consider this in the analysis. As for the studies with non‐standard design (e.g. cross‐over trials, cluster‐randomized trials), we will manage the data according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We will attempt to contact the study authors for missing data. If some information remains unavailable, we will consider both best‐case and worst‐case scenarios.

Assessment of heterogeneity

We will check for statistical heterogeneity among the results of different trials using the Chi² test with significance set at P < 0.1. We will use the I² statistic to assess heterogeneity among the studies in each analysis. We will consider I² greater than 50% to be substantial heterogeneity, and we will seek the potential sources of the heterogeneity (clinical and methodological heterogeneity). We will perform meta‐analysis using the random‐effects model regardless of the level of heterogeneity.

Assessment of reporting biases

We will use the funnel plot method (Egger 1997).

Data synthesis

If we consider the studies to be sufficiently similar, we will carry out a meta‐analysis by pooling the appropriate data using RevMan 5 (RevMan 2014). If there are no suitable studies, we will conduct a narrative summary of study results.

'Summary of findings' table

We will attempt to create a 'Summary of findings' table in the review to report the relevant primary and secondary outcomes using the GRADEpro Guideline Development Tool (GRADEpro GDT). Two review authors (JL, SW) will independently assess the evidence based on the GRADE approach (Atkins 2004), and the methods and recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) .

Subgroup analysis and investigation of heterogeneity

If appropriate data are available, we plan to undertake subgroup analysis according to:

  • severity of initial impairment;

  • stimulation parameters.

Sensitivity analysis

We will perform sensitivity analyses excluding studies:

  • with inadequate concealment of allocation;

  • in which outcome evaluation was not blinded;

  • in which loss to follow‐up was not reported or was more than 10%.