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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2017,  2:140

A vestibular biomarker of manic and depressive phase in bipolar disorder


1 Vest Brain, Centro de Estudios Neuro-Vestibulares, Santiago, Chile
2 Clínica Psiquiátrica, Hospital Clínico, Universidad de Chile, Santiago, Chile
3 Clínica Psiquiátrica, Hospital Clínico, Universidad de Chile, Santiago, Chile; Millenium Institute for Depression and Personality Research, Ministry of Economy, Chile, Macul, Santiago; Psychiatry Department, Tufts University School of Medicine, Boston, MA, USA

Date of Web Publication8-Nov-2017

Correspondence Address:
Ana Marķa Soza
Vest Brain, Centro de Estudios Neuro-Vestibulares, Santiago
Chile
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Source of Support: This study was supported by the Vest-Brain, Centro de Estudios Neurovestibulares; Fund for Innovation and Competitive-ness (FIC) of the Chilean Ministry of Economy, Development and Tourism, through the Millennium Scientific Initiative, Grant Number IS130005., Conflict of Interest: None


DOI: 10.4103/2542-3932.217492

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  Abstract 

Background and objectives: Bipolar disorder (BD) is a neuropsychiatric disorder characterized by cyclic changes in mood between hypoactive, pessimistic (depressive phase) and hyperactive, optimistic (manic/hypomanic phase). Prior studies in major depression patients show that the right side of the vestibular system (inner ear's equilibrium system) is less active compared to the left. It suggests a relationship between mood and abnormal lateralization of the vestibular activity. This exploratory investigation analyzes the right and left vestibular activity in different mood phases of BD and healthy controls.
Design: A transversal cross-sectional study.
Methods: We will study and compare the lateralization of the vestibular activity of BD I or II patients, who match the selection criteria for different mood phases: depression, mania/hypomania, euthymia and healthy controls (6 patients each group).
Outcome measures: For vestibular evaluation, we will use rotary chair technique and electronystagmography. The primary outcome measure is the per- and post-rotatory asymmetry. The secondary outcome measures are the slow phase velocity of the nystagmus, the rhythmicity of nystagmus, and the type of slow ocular tracking.
Discussion: This study addresses the relationship between mood states and abnormal right-left side lateralization of the vestibular activity in BD patients.
Ethics and dissemination: The study protocol was approved by the ethics committee of Servicio de Salud Metropolitano Oriente, in Santiago, Chile on June 21st, 2016. Participants will provide written informed consent prior to participation in the trial.
Trial registration: ClinicalTrials.gov identifier: NCT02827045 on July 6th, 2016.

Keywords: bipolar disorder; manic phase; depressive phase; vestibular marker of mood; biological marker of mood; rotary chair


How to cite this article:
Soza AM, Barroilhet S, Vohringer P. A vestibular biomarker of manic and depressive phase in bipolar disorder. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:140-5

How to cite this URL:
Soza AM, Barroilhet S, Vohringer P. A vestibular biomarker of manic and depressive phase in bipolar disorder. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2018 May 22];2:140-5. Available from: http://www.actnjournal.com/text.asp?2017/2/4/140/217492


  Introduction Top


Background

Bipolar disorder (BD) is a common neuropsychiatric illness that affects 0.1% to 7.5% of the adult population (Dell'Aglio et al., 2013). A chronic condition with devastating consequences for the patients and society. It decreases the productivity of the countries by the loss of useful years due to the disability and also by the loss of valuable years due to premature death by suicide. For each patient, the United States expends $3,400 per year (Fajutrao et al., 2009). About 72% of BD patients have an invalidity pension, and 70% of them are unemployed, which generates necessary costs that reach close to 2 trillion dollars (Marwaha et al., 2013).

BD is characterized by cyclic changes in mood between depression (depressive phase), euphoria/high increased activity (manic phase), and remission phase (euthymic phase).

During the depressive phase, the mood, the interest, and the hedonic capacity decrease significantly. Here, inappropriate negative feelings such as guilt, worthlessness, vulnerability, and loneliness appear with variable levels of distress. Depressive patients usually suffer sleep and appetite disturbances, lack of energy or fatigue. They complain of many difficulties in concentrating, and of cognitive impairment. At this phase, BD patients usually have a negative view of themselves, of the environment and the future. Ideas of death, suicidal ideation or even suicidal attempts are also frequent (Malhi et al., 2007).

Contrariwise, during the manic phase, patients exhibit expansive mood, increased self-esteem or grandiosity, and enhanced physical energy. Increased speed of thinking, social disinhibition, and distractibility are frequent. Also, talkativeness, limited judgment decisions, and involvement in potentially risky situations are common during this state. When these symptoms last for at least 1 week associated with significant social or occupational dysfunction, it corresponds to a manic episode, but if the clinical picture is not that intense, and there is no psychosocial dysfunction, it corresponds to a hypomanic episode.

Between the two extremes (depressive and manic/hypomanic) the patients sometimes pass through relatively normal (euthymic) mood periods of a variable duration. However, even in those periods, the patients may continue presenting alterations in cognitive functioning and showing varying degrees of psychosocial dysfunction (Vöhringer et al., 2013).

As most of psychiatric disorders, the pathophysiology of BD is unknown. Therefore, no biological markers are currently available for BD.

The cyclic nature of this disease has led to postulate that the origin of BD may be associated with alterations in the biological clock that controls the circadian rhythms. However, most of the genetic studies looking for mutations in these genes have been inconclusive (Gonzalez, 2014).

The studies of the brain activity trying to identify a particular pattern for distinct mood phases of BD have been difficult and often unfruitful. In one investigation, Blumberg et al. (1999) studied a small group of six BD patients undergoing in a manic phase using PET scan demonstrating a diminished activation of the right rostral orbitofrontal cortex and lower orbitofrontal activity. Further investigations in manic patients also reveal higher activity in the left dorsal anterior cingulate region and the left head of the caudate (Blumberg et al., 2000). According to this findings, Rubinsztein also demonstrated increased activity in the left dorsal anterior cingular region and diminution of the right frontal polar activity in manic patients during decision-making tasks (Rubinsztein et al., 2001). Additional functional MRI studies showed blunted right ventrolateral prefrontal cortex (VLPFC) activity in mania in the Stroop test of words, and an enhancement of left VLPFC function in the depressive phase (Blumberg et al., 2003). Altshuler et al. (2005) found increased activity in the left amygdala, and a bilateral diminution of the orbitofrontal activity during mania episodes. Disappointingly we have no comparable studies on the depressive phase of BD.



Concerning biochemical markers of mood states, a meta-analysis concludes that brain-derived neurotrophic factor (BDNF) is diminished in both the depressive and manic phase, being relatively healthy in euthymic periods. However, the high fluctuations of its values make it difficult to act as a marker (Fernandes et al., 2015). Another study with a battery of 320 proteins suggests that they could serve as a marker of status for each phase of the disease (Frye et al., 2015).

Previous studies showed that monopolar depression exhibits a particular pattern of vestibular activity (right side lower than left) that can be measured and quantified through vestibular exams (Soza Ried and Aviles, 2007; Lithgow et al., 2015; Maller et al., 2014). These investigations allow hypothesizing that there is a relationship between abnormal mood and lateralization of the vestibular activity.

Considering that there is an abnormal vestibular pattern for unipolar major depression during depressive episodes, the objective of the present study is to determine if there are specific vestibular patterns for each phase of BD (depression/mania). It also aims to compare the vestibular models of the BD's depressive phases with those of monopolar unipolar depression and compare BD's euthymic phase to healthy controls vestibular response.

A biological marker capable of precisely determining whether the patient is in the depressive phase would allow identifying the initial stages of the period, thereby reducing the negative impact of this disease. Early detection of depression would in turn favor early treatment and would decrease the occurrence of suicides. BD has been shown to have the highest suicide rate among psychiatric illnesses, from 15% (Simon et al., 2007) up to 20% (Goodwin et al., 2007), generating approximately 25% of all suicides (American Psychiatric Association, 2013). A status marker would also allow the early detection of manic phases of the disease for the prompt and timely treatment. It would reduce the costs associated with these episodes. At the same time, a status marker would allow monitoring the evolution of the disease and qualify the effectiveness of the treatments. The identification of a vestibular pattern for each phase of the BD would help to determine objectively which phase the patient is. Also, would serve to monitor the response to treatments objectively and study the resistance or control the symptomatic improvement. It would help the process of differential diagnosis between mood disorders and other psychiatric disorders, and between subtypes of mood disorders.

BD is a common neuropsychiatric condition worldwide that show a cyclic alteration of the mood between depression and mania. It has devastating consequences, affecting the stability of the patient and his family, debilitating the psychiatric-psychological development of the new generations. As well, BD is the origin of massive expenditures for the countries regarding disability pensions, high unemployment rates, suicide and medical leaves. The pathophysiology of this disease is unknown, and there are no status markers for it, neither for each mood phase of the disorder. In the clinical practice, the indicated treatment often fails to decrease depression and manage the euphoria. Also in many cases, it is not possible to prevent the occurrence of new episodes. This failure is evidenced by the high rates of disability, license, unemployment and suicide pensions. The demonstration of a biological marker consisting of different patterns of vestibular activity between mood phases of bipolar depression and monopolar unipolar depression would allow making accurate therapeutic indications. It would eventually increase the understanding of the physiopathology of this disease, approaching the development of treatments focusing on the restoration of the vestibular alterations.

Objectives

This trial study aims to describe and compare the vestibular activity between depressive, manic/hypomanic and euthymic phases of BD. Also, we aim to compare the pattern of vestibular activity of the depressive phase of the BD with that of the unipolar major depression, and the vestibular activity of the euthymic phase of BD with that of healthy controls.


  Methods/Design Top


Study Design

The design of this research corresponds to a cross-sectional study. It will be performed in the target population; patients with BD in the depressive phase, in the hypomanic phase, and in the euthymic phase. This methodological design allows us to determine if there is a particular vestibular activity pattern for each phase of BD. Psychiatrists will recruit patients who meet the inclusion criteria for the study.

Study setting

The study will be carried at two different settings; the selection and recruitment of patients will be at the outpatient clinics of the psychiatrists. The vestibular tests will be assessed at Vest Brain, Centro de Estudios Neuro-Vestibulares in Santiago, Chile.

Study procedure

After a baseline clinical evaluation, patients with a clinical diagnosis of BD Type I and II and healthy controls will be recruited. The patients will be informed of the nature of the research and its procedures. Candidates who complete the screening, meet the inclusion criteria, voluntarily wish to participate and sign the Informed Consent, may be integrated into the investigation. Afterwards, they will be referred to Vest Brain, Centro de Estudios Neuro-Vestibulares where they will be tested for vestibular function. It is estimated that the psychiatrists attend approximately 150 patients with BD per year. From this universe, the first six patients who meet the inclusion criteria for each group (depression, mania/hypomania, euthymia), as well as six healthy subjects that meet the inclusion criteria will be selected.

The vestibular evaluation will be made in a blinded form, that is to say, the person who performs and informs the vestibular exam will be blinded to group information. This research does not contemplate the follow-up of patients but rather aims to observe the pattern of vestibular functioning in patients with BD attending a psychic episode ([Figure 1]).
Figure 1: Flow chart of the study.

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Study participants

The study will investigate three different groups of BD patients corresponding to depression, hypomanic/manic, and euthymic phase groups and a group of healthy controls. Only subjects who meet the inclusion and exclusion criteria, and sign the informed consent will enter into the study.

Inclusion criteria

BD patients coming for either group of the study should meet the following criteria:

  • Have a diagnosis of BD Type I or Type II based on clinical evaluations confirmed by the results of the Structured Clinical Interview for the DSM-IV Manual of Mental Illnesses-TR, Patient Version (SCID-P) for mood disorders (American Psychiatric Association, 2013) administered by two experienced psychiatrists
  • Must have presented at least one manic, hypomanic or mixed episode of sufficient intensity to have required treatment with mood stabilizers or antipsychotics
  • Age between 16 and 60 years
  • May be taking any drug for underlying diseases
  • Absence of mixed status: Koukopoulos Mixed Scale score (Koukopoulos and Sani, 2014) less than 14
  • No neurological disease
  • The lack of personality disorder diagnosed according to clinical diagnosis of an experienced psychiatrist
  • No alcohol or drug abuse in the last 3 months
  • Not pregnant
  • No change of medicines within 2 days before the consultation
  • Sign informed consent


Depression phase group: to be included in the depressed group, BD patients, should present a minimum score of 20 on the Montgomery-Asberg Depression Scale (MADRS), The scale to be used in this study corresponds to the MADRS translated into Spanish that was validated (Lobo et al., 2002).

Mania/hypomania phase group: to be included in the manic group BD patients should have a minimum score of 20 on the Manic Scale of Young (YMRS) (Young et al., 1978; Colom et al., 2002).

Euthymic phase group: to be included in the euthymic group, BD patients, and healthy controls should have less than 7 points on both scales (MADRS and YMRS) and less than 14 points in the KMS.

Healthy group: to be included in the healthy group, healthy subjects shouldn't have a history of mental disabilities, nor of personality disorders, have a stable work, have less than 7 points on both scales (MADRS and YMRS) and less than 14 points in the KMS.

Exclusion criteria

Patients with a KMS score greater than 14 will be excluded from the study. The mixed state corresponds to the presence of symptoms of depression and mania simultaneously in the same patient. This kind of patients should be excluded from the study.

The exclusion criteria include a history of dependence on alcohol or substances in the last three months, increased risk of suicide, or any decompensated symptomatic or untreated medical illness, pregnancy, history of epilepsy, neurological disease, and the presence of personality disorders.

Withdrawal criteria

The patients will be voluntarily withdrawn from the study if declining continued treatment.

Recruitment

Eligible patients have to sign the informed consent at the psychiatric consultation and then will be referred to the Centro de Estudios Neuro-Vestibulares for vestibular exams.

Baseline analysis

We will complete a baseline analysis considering age, sex, manual preference, type of BD, actual and previous medications and treatments and years since the first illness symptom.

Interventions

Each patient selected by the psychiatrist should telephone the Neuro-vestibular Center to schedule an hour for the vestibular test that should be performed up to 48 hours after being evaluated by the psychiatrist.

In the Neuro-vestibular Center, the patient's data will be collected. After that, an explanation of the vestibular test procedure will be provided for every patient. For the recording of the signal, three electrodes with conductive gel will be placed, one in each temple and the front. Then the eye movements will be calibrated through ordering the patient to look at the different points on the screen. The patient should then close his eyes and tilt his head down 30°, while the chair begins to turn to the right with an acceleration of 25°/s for 4 seconds, and continue with the turning of the chair into the opposite direction with the same parameters.

Outcome measures

This study will evaluate the vestibular function, assessed by electronystagmography. The vestibular stimuli consist in horizontal rotation provided to the subject while sitting in the computer-controlled Vest Brain Rotary Chair (Vest Brain Ltda., Santiago, Chile) certified by the Public Institute of Health (ISP). Specifically, the analysis of the vestibular nystagmus generated by the right and left rotation will be performed. The speed of the slow phase of the nystagmus caused by the right turn will be analyzed and compared with that generated by the left turn.

Primary outcome measures

The primary outcomes are: 1) Per-rotatory asymmetry: the quotient between the speed of the slow phase of nystagmus during right rotation (right per-rotatory) and left rotation (left per-rotatory). 2) Post-rotatory asymmetry: the quotient between the slow phase velocity of the nystagmus at the end of the left turn (left post-rotatory) and the end of the right turn (right post-rotatory)

Secondary outcome measures

Secondary outcomes include the slow phase velocity of the nystagmus, the rhythmicity of nystagmus, the type of slow ocular tracking.

Statistical analysis

For the study of the statistical differences between pairs of groups, we will use U Mann-Whitney tests using STATA 12.0 software (Stata Corp., Texas, USA).

A previous study reported a 30% difference between depressed patients receiving vestibular stimulation and placebo controls (Soza, 2014). Based on it, a sample size of six manic, six depressives, six euthymic and six healthy controls will be sufficient to find a significant difference with 80% power and alpha of 5% of two sides. The trial will include six patients of each group. It was estimated that for a 95% power that quantity could define differences between groups.

Data collection

The electronystagmograph records that contain the vestibular activity of the patients will be stored in the computer for reanalysis.

An expert medical technologist technician will analyze each registry. From each vestibular response (left and right rotation), the slow phase velocity of the six most representative nystagmus will be averaged. Data of each group will be collected in a database.

A trained statistician researcher will analyze the database.

Ethical requirements and dissemination

The Ethical Committee: Comité de Etica Científico Adultos, Servicio de Salud Metropolitano Oriente, Hospital Salvador in Santiago, Chile, approved the study on June 21st, 2016. The committee will audit the progression of the research. The results of the investigation will be disseminated on peer review scientific journals. The trial will be reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist (Additional file 1 [Additional file 1]).

Confidentiality

All patient data will be kept confidential.


  Discussion Top


Major depression presents a particular vestibular pattern of activity that corresponds to a biological marker of status (Soza Ried and Aviles, 2007; Maller et al., 2014; Lithgow et al., 2015). The present study aims to measure whether there are distinct and characteristic patterns of vestibular activity for each of the BD's different mood states that could serve as state markers of phase.


  Trial status Top


This research is currently recruiting patients.[24]

 
  References Top

1.
Altshuler L, Bookheimer S, Proenza MA, Townsend J, Sabb F, Firestine A, Bartzokis G, Mintz J, Mazziotta J, Cohen MS (2005) Increased amygdala activation during mania: a functional magnetic resonance imaging study. Am J Psychiatry 162:1211-1213.  Back to cited text no. 1
    
2.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington DC: American Psychiatric Association.  Back to cited text no. 2
    
3.
Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, Charney DS, Gore JC, Krystal JH, Peterson BS (2003) A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry 60:601-609.  Back to cited text no. 3
    
4.
Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, White T, Epstein J, McBride PA, Eidelberg D, Kocsis JH, Silbersweig DA (2000) Increased anterior cingulate and caudate activity in bipolar mania. Biol Psychiatry 48:1045-1052.  Back to cited text no. 4
    
5.
Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T, Epstein J, Isenberg N, McBride PA, Kemperman I, Emmerich S, Dhawan V, Eidelberg D, Kocsis JH, Silbersweig DA (1999) Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder. Am J Psychiatry 156:1986-1988.  Back to cited text no. 5
    
6.
Colom F, Vieta E, Martínez-Arán A, Garcia-Garcia M, Reinares M, Torrent C, Goikolea JM, Banús S, Salamero M (2002) Spanish version of a scale for the assessment of mania: validity and reliability of the Young Mania Rating Scale. Med Clin (Barc) 119:366-371.  Back to cited text no. 6
    
7.
Dell'Aglio JC Jr, Basso LA, Argimon, II, Arteche A (2013) Systematic review of the prevalence of bipolar disorder and bipolar spectrum disorders in population-based studies. Trends Psychiatry Psychother 35:99-105.  Back to cited text no. 7
    
8.
Fajutrao L, Locklear J, Priaulx J, Heyes A (2009) A systematic review of the evidence of the burden of bipolar disorder in Europe. Clin Pract Epidemiol Ment Health 5:3.  Back to cited text no. 8
    
9.
Fernandes BS, Molendijk ML, Köhler CA, Soares JC, Leite CM, Machado-Vieira R, Ribeiro TL, Silva JC, Sales PM, Quevedo J, Oertel-Knöchel V, Vieta E, González-Pinto A, Berk M, Carvalho AF (2015) Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med 13:289.  Back to cited text no. 9
    
10.
Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM (2015) Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry 5:e689.  Back to cited text no. 10
    
11.
Gonzalez R (2014) The relationship between bipolar disorder and biological rhythms. J Clin Psychiatry 75:e323-331.  Back to cited text no. 11
    
12.
Goodwin FK, Jamison KR, Ghaemi SN (2007) Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression: Oxford University Press.  Back to cited text no. 12
    
13.
Koukopoulos A, Sani G (2014) DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand 129:4-16.  Back to cited text no. 13
    
14.
Lithgow BJ, Garrett AL, Moussavi ZM, Gurvich C, Kulkarni J, Maller JJ, Fitzgerald PB (2015) Major depression and electrovestibulography. World J Biol Psychiatry 16:334-350.  Back to cited text no. 14
    
15.
Lobo A, Chamorro L, Luque A, Dal-Ré R, Badia X, Baró E, Grupo de Validación en Español de Escalas Psicométricas (GVEEP) (2002) Validation of the Spanish versions of the Montgomery-Asberg depression and Hamilton anxiety rating scales. Med Clin (Barc) 118:493-499.  Back to cited text no. 15
    
16.
Malhi GS, Ivanovski B, Hadzi-Pavlovic D, Mitchell PB, Vieta E, Sachdev P (2007) Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia. Bipolar Disord 9:114-125.  Back to cited text no. 16
    
17.
Maller JJ, Lithgow B, Gurvich C, Haghgooies S, Pouya OR, Fitzgerald PB, Kulkarni J (2014) Separating mental disorders using vestibular field potentials. Arch Neurosci 2:e19257.  Back to cited text no. 17
    
18.
Marwaha S, Durrani A, Singh S (2013) Employment outcomes in people with bipolar disorder: a systematic review. Acta Psychiatr Scand 128:179-193.  Back to cited text no. 18
    
19.
Rubinsztein JS, Fletcher PC, Rogers RD, Ho LW, Aigbirhio FI, Paykel ES, Robbins TW, Sahakian BJ (2001) Decision-making in mania: a PET study. Brain 124:2550-2563.  Back to cited text no. 19
    
20.
Simon GE, Hunkeler E, Fireman B, Lee JY, Savarino J (2007) Risk of suicide attempt and suicide death in patients treated for bipolar disorder. Bipolar Disord 9:526-530.  Back to cited text no. 20
    
21.
Soza AM (2014) Estimulación vestibular como terapia coadyuvante en la depresión mayor. In: Fonis 10 Años Apoyando La Investigación Aplicada En Chile, p 89: Depsrtamento de Comunicaciones de CONICYT.  Back to cited text no. 21
    
22.
Soza Ried AM, Aviles M (2007) Asymmetries of vestibular dysfunction in major depression. Neuroscience 144:128-134.  Back to cited text no. 22
    
23.
Vöhringer PA, Barroilhet SA, Amerio A, Reale ML, Alvear K, Vergne D, Ghaemi SN (2013) Cognitive impairment in bipolar disorder and schizophrenia: a systematic review. Front Psychiatry 4:87.  Back to cited text no. 23
    
24.
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429-435.  Back to cited text no. 24
    

Author contributions
AMS designed the study and wrote the paper, SB and PV revised and approved the paper. SB and PV are responsible for the recruitment of the participants. Vestibular tests: AMS.
Conflicts of interest
The authors declare no conflicts of interests.
Research ethics
The study protocol was approved by the Ethics Committee of SSMO (Servicio de Salud Metropolitano Oriente) in Santiago, Chile on June 21st, 2016.
Declaration of participant consent
The authors certify that they will obtain all appropriate participant consent forms. In the form, participants will give their consent for their images and other clinical information to be reported in the journal. The participants understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Data sharing statement
No data is reported in the article.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.
Additional file
Additional file 1: SPIRIT checklist.


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