Örebro University School of Medicine Degree project, 30 ECTS May 24th, 2017
Author: Martina Johansson
Bachelor in Medicine
Supervisor: Anders Westerborn - Consultant
Department of Otorhinolaryngology, Head & Neck Surgery, Örebro, Sweden
Evidence-based Management of
Epistaxis caused by
Hereditary Hemorrhagic Telangiectasia
Introduction: Hereditary Hemorrhagic Telangiectasia is a rare disorder causing malformation
in the vessel wall. The most common manifestation is epistaxis and it is often very hard to manage. Many therapies have been tried but there is no agreement on which one to prefer. The vascular malformation can also afflict other organs and potentially cause severe complications.
Aim: To investigate treatment alternatives for epistaxis caused by hereditary hemorrhagic
Methods: Systematic review. PubMed, Scopus and Cochrane were interrogated February
2017 with the search terms: (Hereditary hemorrhagic telangiectasia OR Osler Weber Rendu) AND (management OR (epistaxis AND therapy)). The articles were quality assessed using SBU-templates followed by evidence gradation using GRADE. GRADE II-IV articles were included.
Results: Of in total 500 search results, 43 publications were included. Twenty-five GRADE II
articles, 13 GRADE III and five GRADE IV articles.
Conclusion: There is a great risk of publication bias and there are few articles with high level
of evidence. Laser is the surgical option with strongest evidence and ought to be used as first choice therapy. Nasal closure and nasal dermoplasty are effective alternatives for selected cases with severe, intractable epistaxis. Bevacizumab injection is the medical option with strongest evidence, followed by tranexamic acid. Nasal lubricants seem to be an alternative worth trying since it does not have any complications and sometimes have effect.
HHT – Hereditary Hemorrhagic Telangiectasia AVM – Arteriovenous Malformation
CAVM – Cerebral Arteriovenous Malformation PAVM – Pulmonary Arteriovenous Malformation HAVM – Hepatic Arteriovenous Malformation VEGF – Vascular Endothelial Growth Factor
SBU – Swedish agency for health technology assessment and assessment of social services GRADE – Grading of Recommendations Assessment, Development and Evaluation APC - Argon Plasma Coagulation
YAG - Yttrium Aluminium Garnet ND – Nasal Dermoplasty
ESS – Epistaxis Severity Score KTP – Potassium Titanyl Phosphate Hb – Hemoglobin
TXA – Tranexamic Acid
Table of content
1. Introduction ... 1
1.1 Background ... 1
1.2 Aim ... 2
2. Material and Methods ... 2
2.1 Eligibility criteria ... 2 2.2 Information search ... 3 2.3 Ethical considerations ... 4 3. Results ... 4 3.1 The search ... 4 3.2 Treatment alternatives ... 4 4. Discussion ... 6 4.1 Surgery ... 6 4.2 Medicine ... 8 4.3 Conservative ... 11 4.4 Limitations ... 11 4.5 Conclusion ... 12 5. Acknowledgements ... 12 6. References ... 12
1. Introduction1.1 Background:
Hereditary Hemorrhagic Telangiectasia (HHT) is a hereditary disorder with malformations in the vessel wall which often lead to severe epistaxis – nasal bleeding, sometimes causing anemia and requires blood transfusion. The malformations can also afflict the lungs, liver and brain sometimes causing severe complications such as hypoxemia, heart failure, cerebral stroke, among others. 
HHT, also known as Morbus Osler Weber Rendu, is inherited in an autosomal dominant manner. The condition afflicts 1/5000-8000. Known mutated genes associated with the condition are encoding for the protein Activin receptor Like Kinase – 1 (ALK-1) respectively Endoglin involved in the superfamily Transforming Growth Factor–β (TGF- β) which is crucial in the endothelial signal pathway. [2,3] These mutations results in a distension of the blood vessel lumen and thin blood vessel walls. The result is vessel malformations of various extension. Smaller malformations have capillaries between the arteries and the veins – these are called telangiectasias. The larger malformations lack capillaries, instead they have defective anastomoses combining the arteries and veins – these are called Arteriovenous Malformations (AVMs). AVMs are often found in the lungs, liver or brain. The smaller telangiectasias are usually located in the nasal septum, oral mucosa or gastrointestinal mucosa.
The most common manifestation is epistaxis and it usually debuts at an age of 10-20 years and the symptoms progress with time.  Recurrent and abundant epistaxis is present in 95 % of all HHT patients and is sometimes so profuse it can be life threatening. Gastrointestinal malformations are present in about 80 % although only 25 % cause symptomatic bleeding in the digestive system. Both epistaxis and gastrointestinal bleedings are often causing anemia requiring iron supplementation or blood transfusions.  Mucocutaneous telangiectasias are present in about 75 % of HHT patients, common locations are the lips, buccal and tongue mucosa, conjunctiva of the eye and fingertips. Telangiectasias on these locations seldom ends up in hemorrhages of clinical relevance. 
2 Cerebral Arteriovenous Malformations – CAVMs are found in 4-23 % of all HHT patients. [5,7] However, neurological symptoms including ischemic events are more commonly caused by Pulmonary Arteriovenous Malformations – PAVMs.  PAVMs are present in 15-50 % of all HHT patients and are associated with life-threatening complications such as stroke,
cerebral abscesses, hemoptysis, hemothorax as well as desaturation, cyanosis and clubbing.  Another manifestation is Hepatic Arteriovenous Malformations – HAVMs, they are present in 32-78 % of HHT patients sometimes causing complications such as high output heart failure, portal hypertension and more rarely biliary necrosis. 
A variety of treatment alternatives is available. Epistaxis caused by HHT is in the acute setting mainly handled with nasal packing, manual pressure and fluid resuscitation – a management much comparable with management of ordinary epistaxis. There is a great variety of strategies to manage epistaxis caused by HHT in the long term. On one hand, there are medical alternatives such as estrogen, anti-estrogen (tamoxifen), vascular endothelial growth factor – inhibitors (Anti-VEGF), thalidomide, tranexamic acid among others. On the other hand, there are surgical procedures such as lasers, coagulation, coblation, nasal
dermoplasty, embolization and Young´s procedure where the nasal vestibule is closed. 
The aim is to investigate different treatment alternatives for epistaxis caused by HHT in the literature. The collected data will be the basis for a regional medical program for the
department of Otorhinolaryngology at Örebro University Hospital.
1. Material and Methods2.1 Eligibility criteria
• Studies concerning treatment of HHT-caused epistaxis • GRADE II-IV articles
• English text articles • Primary studies
3 Exclusion criteria:
• Articles without abstract • GRADE I articles • Non-human studies • Duplicate studies • In vitro studies • Non-english studies 2.2 Information search:
The information search was conducted on the databases PubMed, Cochrane and Scopus. Used search terms were combined as follows: (Hereditary hemorrhagic telangiectasia OR Osler Weber Rendu) AND (management OR (epistaxis AND therapy)). In addition, filters for English, Abstract, Human and year 2000-2017 were used.
The search on PubMed was performed 2017-02-14 and yielded 290 articles. The search on Cochrane was performed 2017-02-01 and yielded 17 articles. The search on Scopus was performed 2017-02-13 and yielded 193 articles.
Initially a selection based on title was performed, followed by a selection based on the
abstract. Articles selected from their abstract were read in full text, and if assessed as relevant an estimation regarding the quality of the study was performed. This estimation was based on SBU´s (Swedish agency for health technology assessment and assessment of social services) templates for assessment of study quality. A final graduation of evidence was conducted using the GRADE system - Grading of Recommendations Assessment, Development and
Evaluation. This system administers a fourgrade scale of evidence: I – insufficient, II -limited, III -moderately strong, IV – strong. A randomized controlled trial starts on IV on the scale and an observational study starts on II.  All relevant articles with GRADE II-IV was included in this study, articles assessed as GRADE I were excluded.
Since the study is based on already published articles the risk of overstep ethics and secrecy limitation should be quite minute. Even so, focus will be put on the articles ethical
considerations of the included articles.
2. Results3.1 The search:
The selection of articles is presented in figure 1. A total of 500 articles were identified. After
selection on titles, abstracts and eligibility criteria 84 articles were read in full text and 29 were excluded due to irrelevance for this study. Of the 55 articles remaining, twelve were assessed as GRADE 1 and were therefore excluded. [11-22] The 43 articles remaining were assessed as relevant and with GRADE II-IV and were included. Of these 43 included articles 25 were assessed as GRADE II articles, 13 were GRADE III and five GRADE IV.
3.2 Treatment alternatives:
Table 1 is presenting included articles investigating the effect of different therapies and their GRADE, study population and documented effect. A summation of all the articles concerning treatment is available in Appendix 1.
Figure 1, flow chart describing numbers of articles in the selection steps.
Table 1, Describing numbers of included articles for respective treatment alternatives and results of the articles. GRADE II-IV (limited strong) is included.
number of Included articles.
Articles with result of statistical significance (Author, GRADE, study population) Articles with beneficial trends* (Author, GRADE, study population) Articles without positive effect (Author, GRADE, study population) SURGERY Embolization 3 [23-25] 1 (Braak, II, 12) 2 (Layton, III, 22) (Andersen, II, 22) Cauterization 2 [26,27] 2 (Dabiri, II, 5) (Ghaheri, II, 27) YAG (yttrium aluminium garnet ) – laser 3 [28-30] 1 (Karanpantzos, II, 27) 1 (Kuhnel, II, 30) 1 (Luk, IV, 11)
APC – Argon Plasma laser. 4 [31-34] 2 (Pagella, III, 26) (Sadick, II, 52) 1 (Pagella, II, 43) 1 (Hitchings, III, 29) Laser others Diode Biometric 2 [35,36] 2 (Fiorella, II, 24) (Jorgensen, III, 29) Nasal dermoplasty 4 [34,37-39] 1 (Fiorella, III, 66) 1 (Ichimura, II, 15) 1 (Hitchings, III, 29)
Nasal dermoplasty and Timolol 1  1 (Ichimura, III, 11) Sclerotherapy 3 [41-43] 2 (Morais, II, 45) (Boyer, III, 17) 1 (Boyer, II, 7) Young´s procedure 2 [34,44] 1 (Hitchings, III, 8) 1 (Richer, III, 43) Coblation 2 [30,45] 1 (Mortuaire, III, 16) 1 (Luk, IV, 11) CONSERVATIVE
Diet and lifestyle 1  1 (Silva, II, 666) Sesame/rose geranium oil 1  1 (Reh, II, 20) MEDICINE Bevacizumab 8 [48-55] 4 (Simonds, III, 19) (Dheyauldeen, II, 8) (Guldmann, II, 6) (Karnezis, II, 32) 1 (Riss, IV, 15) 1 (Dupuis-Girod, IV, 40) Tranexamic acid 4 [55-58] 3 (Geissthoff, III, 22) (Zaffar, II, 29) (Gaillard, IV, 118) Anti-estrogen 2 [59,60] 2 (Yaniv, II, 46) (Yaniv, II, 25) Estrogen 2 [55,61] 1 (Minami, II, 5) Thalidomide 3 [62-64] 2 (Peng, II, 5) (Invernezzi, III, 31) 1 (Hosman, II, 12) N-acetylcystein 1  1
(de Gussem, II, 43)
* The term beneficial trends involve results without calculation of statistical significance or results close to but not quite reaching statistical significance.
4. Discussion4.1. Surgery:
Argon plasma coagulation (APC) has been shown to be effective when it comes to reducing severe epistaxis dependent on blood transfusions. In one study HHT-patients required fewer units of blood after APC and the effect lasted for nearly two years.  Another,
questionnaire based study found that 90 % would do the procedure again and 92 % experienced reduced epistaxis.  Another study found that APC with following topical estrogen application is an effective way to reduce epistaxis in patients with HHT.  Hitchings et al. compared different treatment alternatives and found no improvement of statistical significance for APC laser and stated that 14 % of the patients in the APC group were improved but just as many experienced worsened epistaxis. 
Yttrium Aluminium Garnet -laser (YAG) is another commonly used laser alternative which has shown to be effective in patients with mild to moderate epistaxis due to HHT. In a study with seven participants the epistaxis was improved with statistical significance in 6/10 criteria measured.  In one study 30 patients with intractable epistaxis received YAG-laser
treatment at individually set intervals, the patients went from daily epistaxis to epistaxis every 7-14 days.  Luk et al. conducted a study comparing coblation and YAG-laser and found no changes on Epistaxis Severity Score (ESS - a validated scoring tool for epistaxis) for either group. 
Diode laser and biometric laser have also been shown to reduce epistaxis in smaller studies, one of them with effect of statistical significance up to 6.5 months after intervention. [35,36]
The evidence for laser treatment for HHT-caused epistaxis is relatively strong. Serious adverse effects are seldom reported. The effect is various but there is reason to believe that laser is a good first choice alternative.
Two small studies were included, both pointing towards trends of effect. The first study found that facial pain is a common side effect and one patient had cerebrospinal fluid leakage during the intervention.  The other study showed that the effect was comparable with laser treatment. 
Evidence for cauterization is limited and lacks studies on long term effects.
Nasal dermoplasty, ND, is a procedure where the nasal mucosa is removed and replaced with skin. A long time follow up of 66 HHT-patients showed that statistically significant less blood transfusions were needed after ND, 53/66 experienced a higher quality of life, 42 % had no epistaxis at all.  Another study found that the graft take rate was 100 % and that all participants were satisfied with the treatment.  One study showed that adverse effects were common such as odor in 78 % of the cases, crusting 72 % and decreased olfaction in 58 %. Even so 86 % experienced higher quality of life than before and only 6 % experienced worse.  Hitchings et al. studied APC along with nasal dermoplasty but found no positive effect.  Timolol application could be of benefit for patients who have undergone nasal dermoplasty earlier without adequate results found one study. The epistaxis was statistically significant improved after three months of daily usage of timolol. 
There is moderately strong evidence for nasal dermoplasty as treatment for HHT-caused epistaxis. However, adverse effects are common.
A case series of 16 HHT patients studied coblation - radiofrequency treatment and found that it reduced frequency and duration of epistaxis without any serious adverse effects. Although the effect only lasted for up to eight weeks for 12 of the 16 patients.  Luk et al. conducted a comparison of coblation and KTP-laser and found no improvement of statistical significance on epistaxis in either group. 
Embolization has been shown to reduce HHT-caused epistaxis with statistical significance when it comes to the outcome measures: frequency, severity and impact of lifestyle . But the effect is reduced and the risk for adverse effect such as facial pain is elevated in patients with HHT compared to other patients troubled with epistaxis. [24,25]
The evidence of embolization as treatment for HHT-caused epistaxis is limited.
Closure of the nasal cavities – Young´s procedure appears to be an effective way to reduce severe epistaxis with statistical significance and the effect is long lasting, found Hitchings et al.  Another study showed that Hb rose with in mean 4.68 g/dL and 83 % of the patients experienced that epistaxis ceased completely. The participants experienced greater wellbeing than before and were likely to do it again. 
The Young´s procedure as a way of reducing and often cease severe HHT-caused epistaxis has moderately strong evidence. The intervention should be used for selected cases after trying several of other alternatives, since it comes with changes in smell and taste.
Sclerotherapy is an intervention where foreign material is injected in the nasal mucosa causing the vessels to shrink and making them less prone to bleed. Three included studies, found that sclerotherapy is an effective method to reduce epistaxis in HHT patients. [41-43] Two of the articles could show an improvement on epistaxis of statistical significance - one retrospective cohort with 45 patients and one prospective study with 17 patients comparing sclerotherapy and continuation of previous therapy. One patient had a septal perforation due to the sclerotherapy. [41,42]
The evidence of sclerotherapy as treatment for HHT is limited. 4.2 Medicine
Bevacizumab (Avastin) is a monoclonal antibody against VEGF and it is the single treatment alternative with most included articles in this study.
Spray: One author conducted a study where six participants were treated with bevacizumab
spray and found that ESS was statistically significant improved first and second month but not after three months of treatment.  A randomized controlled trial investigated bevacizumab spray with different concentrations and found no improvements on the epistaxis. 
Whitehead et al. compared topical tranexamic acid, estrogen, bevacizumab and placebo (saline) and found that all of them improved epistaxis with statistical significance, but there was no difference in effect between any of the therapeutic agents and placebo. 
Injection: One study observed both injections and spray and found that ESS after in mean four
months was statistically significant improved.  Another study investigated bevacizumab injections as an addition to ordinary KTP-laser and found that that patients treated with a combination of these two had statistically significant better effect than KTP laser alone in short term.  A case series with eight HHT-patients treated with bevacizumab injections found statistically significant improved ESS.  However, a randomized controlled trial on the subject found that no outcome was improved with statistical significance and that severe adverse effect such as atrial fibrillation, hypertension and rhinitis were common.  Another study concerning adverse effects found that 5/32 patients receiving bevacizumab injections got septal perforations, all of them had in common that they were treated with laser at the same time. 
The evidence for bevacizumab as treatment for HHT-caused epistaxis is relatively strong, although the results are ambiguous. Injections seems to have stronger evidence than spray, but along with that comes a more serious adverse effect -profile.
Tranexamic acid (TXA) is a commonly used drug to reduce excessive blood loss. Several randomized controlled trials have been made on the area. In one of them, the intervention was 3 g TXA a day for six months which resulted in statistically significant improved ESS but no improvement on Hb.  A randomized trial with crossover technique with same intervention found reduced duration of epistaxis with statistical significance but no other measured
outcomes were improved.  Whitehead et al. compared three ointments, among them tranexamic acid, with placebo (saline) and found that all of them including placebo improved ESS with statistical significance.  One retrospective cohort found that patients treated with systemic or nasal tranexamic acid were statistically significant improved regarding ESS
10 during TXA treatment.  No serious adverse effect were seen in any of the studies
concerning tranexamic acid.
The evidence for Tranexamic acid for treatment is moderately strong.
Thalidomide has anti-angiogenic effects and is therefore a potential therapy for HHT-caused epistaxis. A small case series of five found that ESS were improved with statistical
significance after six months of treatment with 100 mg thalidomide/day.  In another study 31 patients with severe epistaxis were treated with thalidomide 50 -150 mg/day and after about 16 months both Hb and Epistaxis parameters such as frequency, duration and intensity were improved with statistical significance. In this study, one 80-year-old patient died of unknown reasons.  In a retrospective survey Hosman et al. found that 10/12 had
experienced positive effect of thalidomide on epistaxis. However, one patient had aggravated liver hemorrhages and seven patients stopped treatment because of side effects such as skin reactions and neuropathy. 
The evidence for thalidomide as therapy for HHT caused epistaxis is limited, and appear to have an aggressive complication profile.
Yaniv et al. have been studying the effect of tamoxifen, an antiestrogen, as treatment for HHT-caused epistaxis in two studies. Forty-six HHT patients with severe epistaxis were receiving 20 mg/day and after about two years of treatment, Hb, bleeding-score and quality of life was improved with statistical significance.  In a smaller, controlled trial of 25
patients, both frequency and severity were statistically significant improved in the tamoxifen group compared to placebo.  Documented adverse effect were mucous hypertrophy as well as an ovarian cyst, both disappearing after ending medication. [59,60]
Tamoxifen for the use of HHT-caused epistaxis could be a promising alternative in the future, although for now the evidence is limited.
A case series of five patients studied the effect of estrogen ointment twice a day for 3 months and found ESS improved with statistical significance, Hb was not changed.  Whitehead et al. conducted a comparison of topical ointments and showed that all of them, including
11 estrogen, had statistically significant positive effect on ESS but so did placebo, and there was no difference between the placebo group and the estrogen group. 
The evidence for estrogen as treatment for HHT caused epistaxis is low.
De Gussem et al. have been investigating the usage for N-acetylcystein, a prodrug to an antioxidant, 600 mg three times a day for three months time on 43 patients. Frequency and severity were improved with statistical significance and so was the ability to work. 
The evidence for N-acetylcystein as treatment for HHT caused epistaxis is low. 4.1.3 Conservative:
Diet and lifestyle factors:
One included article investigated the impact of life style and diet, in a large HHT population. Lubrication, room humidifier, saline treatments are examples of factors reducing epistaxis Omega 3, anti-allergenic medications and NSAID are examples of factors worsening
epistaxis. Dietary agents high in salicylates such as some spices, chocolate and coffee tend to exacerbate epistaxis. 
The evidence for life style changes for treatment of HHT-caused epistaxis is low.
In a trial 20 HHT-patients was treated with sesame and rose geranium oil and ESS was improved with statistical significance and 10/20 were fully satisfied with the treatment.  As mentioned above in a RCT by Whitehead et al. saline treatment as an placebo control intervention turned out to be of effect for epistaxis just as well as the other intervention groups.  No adverse effects are documented.
The evidence for oil as treatment for treatment for HHT-caused epistaxis is limited. 4.3 Limitations:
There is a great risk of publication bias, all of the treatment categories have studies claiming some sort of effect but there is a risk that those without positive effect are not publishing their results.
12 Few of the articles use the same outcome measures and it is therefore hard to compare them with each other and no meta-analysis could be done. Few of the articles were GRADE III-IV, the great majority of included articled were GRADE II articles, the results are therefore quite unsure.
This study is based on quality assessments, all implemented by one person with little
experience of evaluation of evidence - a risk of assessment bias. To reduce the risk the same person, about two weeks after the last article was assessed, reassessed 10 randomized articles with the same results as the first time. One might also consider it as a strength that the same person assessed all the articles with the same minute experience. Of course, the risk of bias would reduce markedly with another assessor.
One strength is that the search was conducted on three databases in a conclusive manner.
There are few studies investigating treatment of HHT-caused epistaxis with high level of evidence, more research on the area is required. Patients with HHT should be managed in a multidisciplinary team to individually offer optimal treatment. Laser, of different kinds, are the alternative with the strongest evidence and could be used as a first-choice treatment. Bevacizumab injection is the medical option with the strongest evidence, followed by tranexamic acid. For severe, intractable epistaxis nasal dermoplasty and nasal closure are alternatives for selected cases, but the physician should have in mind that it comes with changes in smell and taste. Lubrication of the nose with oil has shown promising results and due to its complication free profile it is an alternative worth trying.
Special thanks to Liz Holmgren, librarian at Örebro University Library for support in the search process and for providing me access to some of the included articles.
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May 15th, 2017. Corresponding author: Martina Johansson, Bachelor of medicine, Örebro University
Me and my co-authors are humbly asking for a couple of minutes of your time.
Hereditary hemorrhagic telangiectasia, HHT, is a disorder causing severe epistaxis, often reducing quality of life with profound measures. To manage the epistaxis many different therapies are used, but there is no agreement what treatment is to prefer.These malformations can also afflict other organs, sometimes causing severe complications such as heart failure and stroke.
This systematic review evaluates treatment alternatives in a conclusive manner. It is thought to be a comprehensive material – a potential basis for further studies and foremost a guidance for those who practice medicine.
Many different treatment alternatives with support in the literature were found. We found that laser is the alternative with strongest evidence, followed by Bevacizumab injections. For selected case with disabling, intractable epistaxis more invasive alternatives like nasal closure and nasal dermoplasty are effective.
Since many literate physicians working with HHT patients are reading your paper, it is the ideal forum for us to publish our paper in, why we exclusively ask for publication in your article.
It would be a great honor for us to publish in such a prestigious and high quality paper. On behalf of all the authors,
Morbus Osler är ett ovanligt tillstånd som drabbar cirka 1/5000.
Rikliga, svårbehandlade näsblödningar är en del av Morbus Osler-patientens vardag. Hos många leder det till ständiga besök på akutmottagningen och kan försämra livskvaliteten ordentligt. Dessa patienter har små missbildningar på blodkärlen vilket gör dem lättblödande. Oftast drabbar de näsan, huden och munnen men kan också drabba andra organ som levern, lungorna och hjärnan och kan då leda till farliga följdtillstånd som stroke och hjärtsvikt. Många behandlingar har prövats för att avhjälpa patientens näsblödning, men det råder inte samförstånd vilken av alla dessa behandlingar som är att föredra.
Den här studien har undersökt vilka behandlingar som blivit testade och vilka resultat dessa visat. Dessa uppgifter kommer användas för att skapa ett vårdprogram till öron-näsa-hals kliniken på Örebro Universitets Sjukhus.
I studien kom vi fram till att det finns många alternativ, både kirurgiska och medicinska, för behandling av näsblödningen. Vi kom fram till att laserbehandling och en relativt ny
antikroppsbehandling är de mest undersöka alternativen med bra effekt. En annan effektiv behandling är att sy igen näsborren, men bara på dem med allra värst sjukdomsbild då det påverkar smak och lukt. Att smörja näsan med olja har god effekt hos vissa och är ofta värt ett försök.
En systematisk litteraturöversikt bearbetar redan publicerat material ytterligare en gång, och sätter med opartiska ögon studier i sin kontext. I många fall kan nya resultat rapporteras och på så vis utnyttjar man studiedeltagarnas och forskarnas redan genomförda ansträngning ännu en gång. Att bearbeta redan publicerat material är också ett effektivt sätt att sätta sig in i forskningsläget och att notera potentiella kunskapsluckor.
Vidare finns risken att man i egenskap av författare av en litteraturöversikt, inkluderar studier vars metod, sekretess eller andra etiska parametrar fallerar. I vår studie har vi lagt särskilt fokus vid om artiklarna dokumenterat etiska överväganden, men flertalet av inkluderade artiklar har inte det. Fler och fler artiklar belyser i etik, vilket underlättar för framtidens systematiska litteraturöversikter att undgå risken att inkludera etiskt förkastliga studier. Vidare kan man tänka sig att patienterna som tackat ja till en studie, inte är informerade om att denna informationen kan användas igen som när man gör en systematisk översikt. Risken att det skulle strida mot deras vilja är emellertid tämligen liten då det är helt avkodad
information och att man använder samma utfallsmått de redan tackat ja till att dela med sig av. Att belysa och forska om syndrom, som vanligen inte är livshotande utan sänker livskvaliteten är av stor vikt. Att kunna förbättra livskvaliteten för människor med livslånga tillstånd
besparar förutom lidande också ekonomiska faktorer som sjukskrivningar och