Treatment of Morton’s neuroma: A systematic review

G Model FAS 1031 No. of Pages 11

Foot and Ankle Surgery xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Foot and Ankle Surgery journal homepage: www.elsevier.com/locate/fas

Review

Treatment of Morton’s neuroma: A systematic review Silvia Valisena, MDa,* , Gianfranco John Petri, MDb , Andrea Ferrero, MDb a b

Service of Traumatology, Regional Hospital of Bellinzona, Via Ospedale, Bellinzona, Switzerland Clinica Luganese Moncucco, Via Moncucco 10, Lugano, Switzerland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 December 2016 Received in revised form 17 February 2017 Accepted 28 March 2017 Available online xxx

Background: The treatment of Morton’s neuroma (MN) can be operative, conservative and infiltrative. Our aim was the evaluation of evidence on outcomes with different types of conservative, infiltrative and surgical treatment in patients affected by primary MN. Methods: The bibliographic search was conducted in MEDLINE, Cochrane Library, DARE. Only studies in English were collected. The last search was in August 2015. Case series and randomized controlled trials (RCTs) assessing patients’ satisfaction or pain improvement at an average follow-up of at least 6 months after treatment of primary MN were included. Two reviewers selected the studies, evaluated their methodological quality, and retrieved data independently. Results: Of 283 titles found, only 29 met the inclusion criteria. Data showed better outcomes with operative treatment. Conclusions: The evaluated case series and few RCTs showed better results with invasive treatment. More and better RCTs which evaluate risk-benefit ratio are required to confirm these results. © 2017 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Keywords: Morton’s neuroma Treatment Surgery Infiltrative Conservative

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Criteria for considering studies for this review 2.1. Data collection and analysis . . . . . . . . . . . . . . . 2.2. Assessment of risk of bias in included studies 2.3. Data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Papers selection . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Description of included studies . . . . . . . . . . . . 3.2. Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Primary outcomes . . . . . . . . . . . . . . . . . . . . . . . 3.5. Conservative treatment . . . . . . . . . . . 3.5.1. Infiltrative treatment . . . . . . . . . . . . . 3.5.2. Operative treatment . . . . . . . . . . . . . . 3.5.3. Secondary outcomes . . . . . . . . . . . . . . . . . . . . . 3.6. Conservative treatment . . . . . . . . . . . 3.6.1. Infiltrative treatment . . . . . . . . . . . . . 3.6.2. Operative treatment . . . . . . . . . . . . . . 3.6.3. Risk of bias in the included studies . . . . . . . . . 3.7. Case series . . . . . . . . . . . . . . . . . . . . . 3.7.1. Randomized controlled trials . . . . . . . 3.7.2. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Viale Stazione 30, Bellinzona 6500, Switzerland. E-mail address: [email protected] (S. Valisena). http://dx.doi.org/10.1016/j.fas.2017.03.010 1268-7731/© 2017 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: S. Valisena, et al., Treatment of Morton’s neuroma: A systematic review, Foot Ankle Surg (2017), http://dx.doi. org/10.1016/j.fas.2017.03.010

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G Model FAS 1031 No. of Pages 11

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5.

4.1. Summary of the evidences Limitations of the studies . 4.2. Conclusions . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .

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1. Introduction

2. Methods

Morton’s neuroma (MN) is a degenerative neuropathy featuring fibrosis of the common interdigital nerve [1]. It is a common pathology mainly affecting middle age women, although there is lack of data on its frequency [2]. Its incidence in UK was 50.2% for men and 87.2% for women per 100,000 of patients presenting to primary care [3]. Four aetiopathogenetic theories have been proposed [4], chronic traction damage [2], inflammatory environment due to intermetatarsal bursitis [5], compression by the deep transverse intermetatarsal ligament [6,7], and ischemia of vasa nervorum [8]. The treatment for MN is initially conservative, progressing to infiltrations and then surgery, if the previous steps fail, according to the therapeutical algorithm available in literature [2,9,10]. The treatments considered as conservative consist in patients’ education on avoidance of tight shoes, manipulation and use of insoles or other special orthotic appliances. The infiltrative treatments include injections of local anaesthetics, steroids or alcohol and percutaneous radio-frequency ablation. The surgical treatments consist of neurectomy or neurolysis, which can be performed open, either via a dorsal or plantar approach, or mini-invasive. The latter is aimed at decompressing the nerve by division of the deep intermetatarsal ligament, either endoscopically or percutaneously. The studies, which assess the results of treatment, have a follow-up from one week [11] to 10 years [12,13]. The length of follow-up allows to identify durable results and to define complications of treatment, failures and recurrences. According to Mann, it takes one year following neurectomy to develop a symptomatic amputation neuroma, after a pain-free postoperative period [14]. The aim of this review is to compare the outcomes of the different types of Morton’s neuroma treatment. Primary outcome defines which treatment provides the best result at an average follow-up of at least 6 months in terms of patients’ satisfaction, improvement of pain and other symptoms. Patients’ satisfaction is based on Johnson’s scale [15] and other scales. Pain was measured with VAS and other scales (number rating scale, NRS). The followup of studies on conservative treatment usually lasts for few weeks to 6 months, in case of infiltrations 6–12 months, for surgical studies it can last for years. To compare the results of all types of therapy we have chosen a 6-month follow-up. Secondary outcome defines the evaluation of complications, recurrences and failures for each type of treatment. Such events are complementary to the primary outcome. It is important to distinguish between mere adverse events and recurrences. The first, such as haematoma, infection, postoperative pain, allergic reactions to injected drugs are only a temporary setback, whereas the second can have a long-term impact on patients’ quality of life.

2.1. Criteria for considering studies for this review

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Studies were identified by searches in electronic libraries, trial registries and bibliographic quotations. Two reviewers (A.F. and S. V.) independently carried out the bibliographic searches and studies’ selections, holding into account the inclusion and exclusion criteria (described later). Cases of disagreement were arbitrated by a third reviewer (G.J.P.). The authors of the selected studies were never contacted. Searches were carried out on MEDLINE (1946 to August 2015), Cochrane Library (1979 to August 2015), DARE (1995 to August 2015), ClinicalTrials.gov and PROSPERO by combining “Morton’s neuroma”, “neuroma”, “surgery”, “infiltrative”, “conservative”, “treatment”. We have included prospective and retrospective case series and randomized controlled trials (RCTs) which assess the results of conservative, infiltrative and operative treatments in patients with diagnosis of primary MN, excluding stump neuroma and recurrences, with a mean follow-up of at least 6 months. We excluded papers in languages other than English, case reports and animal studies. We excluded studies in which X-rays and histology showed that a sizable proportion of patients presented pathologies other than Morton’s (usually bursitis and synovitis) and in which the results were cumulative and did not differentiated the neuroma from the other forms of metatarsalgia. One such study, even if excellent from a methodological point of view, was excluded on account of 31% ultrasound confirmed bursitis [16]. Many studies on primary MN exclude patients with rheumatoid arthritis, diabetes mellitus and foot deformities. Many others do not state whether such conditions are cause for exclusion. A few studies do include some such patients. Because of such disparity we decided not to consider those conditions as exclusion criteria. We did not exclude papers on the basis of publication date or status. We excluded studies which presented bias with overestimation of results, as for protocol analysis in controlled randomized trials. One important requirement for inclusion was that the primary outcome be assessed after a mean follow-up of 6 months. This was an arbitrary choice based on the observation that studies on conservative and infiltrative treatment have a mean follow-up usually inferior to 6 months. Therefore our choice of 6 months allowed us to compare studies on the three types of treatment. Furthermore, it is twice the length of follow-up reported in a previous Cochrane Review [17]. Studies with follow-up periods and outcomes not clearly defined were excluded. The evaluation of the secondary outcome was added to our protocol secondarily because, during selection of the articles, we often noticed that complications and recurrences were either unreported or cumulated as adverse events. Moreover, some authors report reoperation rates without naming their causes. Assessing the correct reporting of complications and recurrences is useful to identify cases of excessively positive reporting of results.

Please cite this article in press as: S. Valisena, et al., Treatment of Morton’s neuroma: A systematic review, Foot Ankle Surg (2017), http://dx.doi. org/10.1016/j.fas.2017.03.010

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283 titles/abstracts – 260 MEDLINE – 13 Cochrane Library – 1 DARE – 8 ClinicalTrials.gov – 1 PROSPERO

7 redundant studies eliminated

276 titles/abstracts examined

235 studies eliminated – 37 full texts not available – 198 not meeting inclusion criteria

41 full texts examined

12 studies not meeting inclusion criteria

29 studies included in the qualitative analysis Fig. 1. Flow chart: procedure for paper selection.

Patients with recurrence or needing further injections or reoperation were defined as failures. The procedure used for the papers selection is described in the flow chart in Fig. 1. 2.2. Data collection and analysis We created a chart for data extraction; it was tested at interim analysis and subsequently implemented with the secondary outcome related columns. The extraction of the data has been performed by two authors in independent way. There have not been cases of disagreements among the analyses of the two authors. From every included study we have drawn out information related to:  demographic data (number of participants, number of MNs affected feet, median age and range for every sample of patients);  clinical data (duration of the symptoms before treatment, type and duration of any previous treatment, average duration and range of the follow-up, type of treatment, numbers of confirmed MNs, numbers of cases confirmed by histological examination, clinical outcomes, complications, therapeutical failures). From the original data set, only the following items were selected: information related to the number of participants, average duration and range of the follow-up, type of surgery, outcomes, complications, failures. We have performed a weighted average in order to reduce the influence of the sample size on the frequency of the outcome for every type of treatment. 2.3. Assessment of risk of bias in included studies We followed the bias assessment process as described in the Cochrane Handbook [18], making it suitable for the case series.

3

For every bias, we defined the level of risk as high, low or indefinite. We drew up a table to evaluate:  the suitability of the study design;  any misclassification bias due to the diagnosis used to define the sample;  information bias, checking if the inclusion and exclusion criteria were described for all the patients;  selection bias, defined as a sequential ordering bias of the patients for the case series and according to the variables pointed out by the Cochrane Handbook for the randomized control trials (RCTs);  performance and detection bias for the RCTs and even for the case series, when they indicated if the blinding for the outcome assessors had been performed for the patients or for the medical staff;  recall bias, evaluation of any patient’s mistake in reporting clinical data;  reporting bias, reporting not in line with the specific statement of the study or omission of any clinical data or results;  attrition bias: this term was used both for RCTs and observational studies; consequently, when this bias was present, the term used in the table was “for protocol analyses”. Case series do not use a rigorous methodology, according to their low level of evidence. Case series with a low risk of results overestimation and with suitable methodological characteristics were included. 2.4. Data synthesis We presented the outcome (in Tables 1 and 2) as an absolute number to perform the weighted average for every column. For this reason, we performed proportions to convert the frequency from relative to absolute when the paper reported the result only in percentage. This conversion was possible only for the papers in which the general number of the studied population was known and a protocol analysis was not performed. We did not perform a meta-analysis to the interim analyses, because most of the studies were observational. It was not possible to perform a meta-analysis for the included RCTs either, because of the high degree of heterogeneity, as already found by other authors [17]. 3. Results 3.1. Papers selection At the beginning of our sensitive research, we had 283 papers. After a first screening we examined 41 full texts. In a second phase, we excluded studies with a high number of patients affected by non-Morton’s metatarsalgia in which the demarcation between the sub-populations was not possible. We only kept the papers in which the number of patients potentially affected by a non-Morton’s metatarsalgia was thought to be very low (less than 5 patients). Some other papers were excluded for different reasons:  studies that described a treatment algorithm without specifying the duration of each stage;  studies that did not describe the outcome in terms of patients’ satisfaction and improving symptoms;  studies that did not use the same outcome measures described in methods;

Please cite this article in press as: S. Valisena, et al., Treatment of Morton’s neuroma: A systematic review, Foot Ankle Surg (2017), http://dx.doi. org/10.1016/j.fas.2017.03.010

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Table 1 Clinical data: outcomes of the included studies (presented as absolute numbers). Study and year

Study design

Surgical treatment Akermark et al. Retrospective case 2008 (Feb) [19] series

Bauer et al. 2015 [36]

Retrospective case series

Participant No.

Mean F-U in months (F-U range)

Treatment

145

n.s. (24–60)

Open

Plantar group: 69 Dorsal group: 56 Open: 26

29 (24–46) 37 (24–60) 24 (24–84)

19

15 (8–21)

Nerve resection-plantar incision Nerve resection-dorsal incision Open neurectomy dorsal incision M.I.S.: Percutaneous metatarsal osteotomies and ligament release Partial neurectomy-dorsal incision

31

44,7 (14–71) 18 (13–54)

Open: excision-dorsal incision (+ adapted shoes/inner soles) Open: neurectomy

M.I.S.: 26 Biasca et al. 1999 [35] Dereymaeker et al. 1996 [21] Faraj et al. 2010 [37]

Kasparek et al. 2013 [22]

Retrospective case series Retrospective case series Retrospective case series

Retrospective case series

36 Plantar group: 20 (Feet No) Dorsal group: 22 (Feet No) 81

Lee et al. 2011 [12] Pace et al. 2010 [38] Park et al. 2013 [39]

Retrospective case 13 series Retrospective case 78 series Retrospective 84 comparative series DTML release: 46 (No of Morton) Osteotomy+ release: 40 (No of Morton) Ruuskanen et al. Retrospective case 45 1994 [13] series Retrospective case 78 Vito et al. 2003 [24] series 55 Prospective case Akermark et al.. 2008 [44] series 17 Barrett et al. 1994 Prospective case [20] series Prospective case 52 Nashi et al. 1997 [23] series Plantar: 26 Dorsal: 26 Valente et al. 25 Prospective case 2008 [40] series 76 RCT Akermark et al. 2013 [45] Plantar group: 35 Dorsal group: 41 Colgrove et al. 44 RCT 2000 [14] Resection: 22 Neuroma intermuscular transposition: 22 Study and year

Study design

Conservative treatment Kilkmartin et al. RCT 1994 [27]

Study and year

Overall Complicationsa Failuresa satisfactiona

68/73 52/59 24/26

4/69 10/56 1/26

0 3/56 1/26

23/26

1/26

1/26

14/19

n.a.

n.a.

26/32

0

1/31

Plantar incision

11/36

1/36

Dorsal incision

6/36

0

30/36

Open: excision-dorsal incision (55 cases with DTML transection; 56 without DTML transection) Open neurectomy-dorsal incision

90/98

73/111

n.a.

13/13

11/13

n.a.

Open: neurectomy-dorsal incision

76/78

18/78

8/78

Open: decompression–dorsal incision for both groups DTML release (Group A)

42/46

3/46

2/46

Metatarsal shortening osteotomy and 40/40 DTML release (Group B)

2/40

0

Open: neurectomy-dorsal incision

47/58

0

5/45

78/82

n.a.

4/82

55/59

3/55

0

6 (9–12)

Open: Decompression with relocation-dorsal incision Open: Nerve resection-plantar incision M.I.S.: Endoscopic decompression

15/17

2/17

n.a.

36 (n.s.)

Open neurectomy

45 (6–72)

Plantar incision Dorsal incision Open: neurectomy-dorsal incision

17/26 21/26 17/25

7/26 4/26 n.a.

1/26 1/26 0

34 (28–42)

Open

34 (28–39) 33 (28–42) n.s. (1–48)

Nerve resection-plantar incision Nerve resection-dorsal incision Open-dorsal incision

32/35 38/41

5/35 6/41 1/44

n.a. 2/41 0

Resection Neuroma intermuscular transposition

19/22 21/22

n.a. 1/22

0 0

180 (120–240) 126 (120–146) 54 (9–96) n.s. (n.s.) 26,2 (24,7–27,7) 26,3 (23,6–29) 72 (24–144) n.s. (n.s–128) 29 (24–46)

Participant No

Mean F-U in months (F-U Treatment range)

Overall satisfaction

23 Supination orthosis: 10 Pronation orthosis: 11

n.s. (n.s.) 10,1

5/10

Study design

Infiltrative treatment Chuter et al. 2013 Retrospective case [41] series Magnan et al. Retrospective case 2005 [42] series

Orthosis Supination with cobra orthosis (treatment A) Pronation with reverse cobra orthosis (treatment B)

11,09

Complications Failures

n.a.

11/23

5/11

Participant No

Mean F-U in months (F-U range)

Treatment

Overall satisfactiona

Complicationsa Failuresa

25

6 (6)

26/30

1/25

3/25

65

36 (24–55)

US-guided radiofrequency ablation Phenol injection-dorsal approach

57/71

0

4/65

Please cite this article in press as: S. Valisena, et al., Treatment of Morton’s neuroma: A systematic review, Foot Ankle Surg (2017), http://dx.doi. org/10.1016/j.fas.2017.03.010

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Table 1 (Continued) Study and year

Study design

Participant No

Mean F-U in months (F-U range)

Treatment

Overall satisfactiona

Complicationsa Failuresa

Moore et al. 2012 [25] Mozena et al. 2007 [26] Musson et al. 2012 [32] Pasquali et al. 2015 [33] Deniz et al. 2015 [43] Fanucci et al. 2004 [28] Hughes et al. 2007 [29] Makki et al. 2012 [30]

Retrospective case series Retrospective case series Retrospective case series Retrospective case series Prospective case series Prospective case series Prospective case series Prospective comparative study

29

13 (3–36)

26/29

1/29

2/29

42

11 (2–24)

Radiofrequency thermoneurolysis Alcohol injection

30/49

3/42

12/42

75

14,3 (6–26)

US-guided alcohol ablation

55/85

1/75

17/75

508

12 (12)

US-guided alcohol injection

400/540

0

n.a.

20

9 (7–15)

12/20

2/20

n.a.

40

10 (n.s.)

US-guided pulsed radiofrequency ablation US-guided alcohol injection

36/40

6/40

4/40

101

21,1 (13–34)

US-guided alcohol injection

91/100

17/101

3/101

43

n.s. (12)

Corticosteroid injections 5/16

n.a.

2/17

8/22

n.a.

4/22

26/39

0

12/39

Markovic et al. 2008 [31]

Prospective case series

G1 (small neuromas): 17 Morton G2 (large neuromas): 22 Morton 35

9 (9)

US-guided corticosteroid injections

M.I.S.: mini-invasive surgery; n.a.: not available (referred to the columns “complications, failures”: one of these was not mentioned nor rated); No: number; n.s.: not stated; a For these columns, satisfaction and symptoms improvement, complications and failure are referred to the number of participant or to the number of feet or to the number of neuromas. This is why the denominator of the fractions can be different from the number of participant. In other cases, if the number of participant includes few bursitis, the denominator of these columns differs because it is referred only to Morton’s neuromas.

 studies that provided data that we could not use to perform weighted average;  studies with protocol analysis. At the end of the skim process, our systematic review was based on 29 studies. 3.2. Description of included studies As shown in Table 1, the 29 studies concerned different approaches to MN: 1 was about the conservative, 11 were about infiltrative [41–45] and 17 about operative treatment [37–40]. They included 17 retrospective case series (11 about operative and 6 about infiltrative treatment); 9 prospective case series (4 about operative and 5 about infiltrative treatment); 3 RCTs (2 about operative and 1 about conservative treatment). The inclusion of only one study on conservative treatment is a limitation, but it must be stressed that most such studies have a follow-up of one month. 3.3. Participants The total number of participants affected by primary MN was 2021, of which 21 treated conservatively, 1041 by infiltrations and 959 surgically. Median age was 43 for conservative and 51,4 for operative treatment. The diagnosis was clinical for 9 studies: 6 about operative [19– 24], 2 about infiltrative [25,26] and one about conservative treatment [27]. In 6 other studies, all concerning infiltrative treatment, the diagnosis was clinical-radiological; in these works, Ultra Sound (US) were used to verify the clinical finding [28–32]. In some studies about operative treatment, the differential diagnosis (DD) was supported by X-rays. In some others, patients underwent X-rays, US and/or MRI for the DD. The ex juvantibus diagnosis, with corticosteroid injection, was used in just one case. In 3 studies the diagnostic method was not mentioned.

Most of the operated patients (10/17 studies) had formerly experienced conservative treatment for 3–12 months, or infiltrative therapy, with 1–3 corticosteroid injections. The patients treated with corticosteroid had previously undergone conservative treatment without improvements. Some of them had received corticosteroid injections without benefit before undergoing radio ablation. 3.4. Treatment Sixteen studies about operative treatment focused on open and 2 on mini-invasive technique. Seven of the 16 studies about open techniques were comparative; 4 of these compared the results of the same operative technique performed via plantar or dorsal approach, while the other 3 evaluated different operative approaches. The most frequent was dorsal. In 14 studies the nerve was excised, whereas in 4 studies it was decompressed by division of the intermetatarsal transverse deep ligament. The follow-up period was 46 months. Six studies concerning infiltrative treatment focused on alcohol injections, 3 on radio-frequency ablation and 2 on corticosteroid injections. The follow-up period was 14 months. The study concerning conservative treatment focused on the use of the orthoses. The follow-up period was about 10.5 months.

Table 2 Primary and secondary outcomes of the included studies. Study type

Satisfaction

Complication rate

Failure rate

Conservative 1 study (C)

Overall 48%

Not available

47%

Infiltrative 11 studies (A, B)

Overall 85% A 74, B 75%

3% 10 studies

14% 10 studies

Surgical 17 studies (A, B, C)

Overall 89% A 91, B 82, C 92%

21% 14 studies

4% 13 studies

A: retrospective studies, B: prospective studies, C: RCT.

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3.5. Primary outcomes The most successful treatments were the operative ones with 89% success rate and the infiltrative ones with 85%. In Table 2 we highlighted that operative treatment gives the best result. 3.5.1. Conservative treatment The use of the orthoses offered some improvement for the 48% of the patients included in the study. 3.5.2. Infiltrative treatment We found 81% success rate for radio-frequency ablation versus 71% success rate for alcohol injections and 51% success rate for corticosteroid injections. 3.5.3. Operative treatment We found 88% success rate for neurectomy versus 94% success rate for the decompression performing weighted averages. No great difference was statistically revealed between dorsal or plantar neurectomy (88% versus 89%). The success rate in the 2 studies on mini-invasive decompression surgery was 88%.

Regarding the attrition bias, we included only few studies in which the over-estimation was not relevant for the general result of the systematic review. For example two patients who missed the follow-up were not included in the final count. The recall bias, typically common in the retrospective case series, was mentioned only in one of the included studies. Despite this, we suppose that this data is underestimated in the table of the methodology quality, due to the difficulty to detect it, unless the authors themselves point out this risk. 3.7.2. Randomized controlled trials The randomization was done, but the technique was not properly described. The concealment of allocation list was not specified in any of the studies. The analysis for protocol was done in few studies. The report of patients’ withdrawal from the study was not always available. The outcome assessors blinding was done in two of the trials. 4. Discussion

3.6. Secondary outcomes

4.1. Summary of the evidences

The presence of complications or recurrences was not always highlighted. In some studies, instead, these data were specified but not properly described or enumerated. We grouped such data into the column “not available data”, as shown in Tables 1 and 2.

This review shows that operative and infiltrative treatments offer the best outcomes. The comparison per study design highlights that surgery has better outcomes than infiltration. The complication rate is higher with surgery, while the recurrence rate is higher with both infiltrative and conservative treatments. These results look similar to those obtained by the Jain et al. narrative review [2]. In that paper, just like in our study, the authors highlighted the incomplete reporting of complications and recurrences. Differently from us, the authors labelled with the terms “complications” not only the proper complications, but also cases of incorrect initial diagnosis, failure of non-operative intervention, inadequate resection and stump neuroma. We prefer to refer to these as “failures”. We deem important to make a clear distinction between the two because of the different impact that they have on the patients’ quality of life: while the majority of complications can be resolved in a short time, failures require more time to be diagnosed and may require an additional intervention. For example, if post-surgical pain persists for many months, it cannot be classified as “complication” anymore, but it could signal a recurrence, or an incomplete, or missing MN resection. Therapeutic algorithms available in literature recommend starting with conservative and infiltrative treatment and contemplating surgery only secondarily [2,10]. According to some authors this also helps in selecting those patients who would benefit from surgery [10]. Others suggest that surgery should be chosen from the beginning in patients with symptoms for at least 6 months [34]. Nonetheless, data from these authors could be biased by recall bias since their results are issued by retrospective studies. Some authors have demonstrated that patients with symptoms for more than a year do not necessarily benefit from surgery [10]. This could depend on the accuracy of diagnosis and it is vital to exclude causes of persistent post-operative pain other than a recurrent MN [36], and use MRI to check the neuroma’s location and size [30,35]. Diameters above 5 mm have been shown to fare better with surgery [35], whereas those below 5 mm do better with infiltration enjoying relief of symptoms up to 6 months [30]. Although our revision has a limit in the inclusion of case series, it is interesting to compare it to the Cochrane one [17]. This included randomised and quasi-randomised controlled trials of interventions which, after Consort [46], are now defined as prospective or cohort studies and, as such, are not as strong as

3.6.1. Conservative treatment The rate of complications was not available because only one study was included, while the rate of recurrences was 47%. 3.6.2. Infiltrative treatment The most frequent complications after infiltrative treatment were haematoma and persistent pain, followed by temporary nerve irritation, infection, severe pain and bruising at the injection site, numbness. One case of allergic reaction to the injection was reported. The global rate of complications was 3%, that is 5% for radiofrequency ablation and 3% for alcohol injections. The complication rate for corticosteroid infiltrations was not available. Symptoms recurred in 14% of patients, 23% after steroid injection, 9% after radio-frequency and 12% after alcohol injections. 3.6.3. Operative treatment The most common postoperative complications were wound infections, followed by hypersensitive scars, keloids, complex regional pain syndrome, persistent postoperative pain, numbness, restriction of physical activities, asymptomatic floating toes, mild stiffness of the metatarsophalangeal joints. The global rate of postoperative complications was 21%, and specifically 25% for neurectomy, 6% for decompression (sectioning of the deep transverse intermetatarsal ligament with/without osteotomy of the metatarsal heads) and 7% for mini-invasive decompression. The whole rate of failures for both open and mini-invasive resection and decompression procedures was 4%. 3.7. Risk of bias in the included studies (Look at Table 3 for methodological appraisal). 3.7.1. Case series The selection bias due to the dominant presence of case series represented the more frequent type of bias in this systematic review.

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Table 3 Methodological appraisal: risk of bias in included studies. Study and year

Miscl. bias

Inform. bias

Select. bias

Perform. bias

Detect. bias

Attrition bias

Report. bias

Clinical diagn.

Inclusion– exclusion criteria state

Type of randomization and sequence reported; concealment of allocation list n.s.

Not stated if blinded outcome assessors

Lost to follow up reported; per protocol analysis

All outcomes reported; for p protocol analysis (few withdrawals hence not relevant)

Low risk of bias

Low risk of bias

Low risk of Unclear risk of bias bias

No blinding of patient/ personnel Low risk of bias

Unclear risk of bias

Unclear risk of bias

High risk of bias

Appropr. study design

Miscl. bias

Study Appropr. design study design

Conservative treatment Kilkmartin RCT Yes et al. 1994 [27]

Study and year

Study design

Infiltrative treatment Retrosp. Yes Chuter case et al. series 2013 [41] Low risk of bias Magnan et al. 2005 [42]

Moore et al. 2012 [25]

Mozena et al. 2007 [26]

Musson et al. 2012 [32]

Pasquali et al. 2015 [33]

Retrosp. case series

Retrosp. case series

Retrosp. case series

Retrosp. case series

Retrosp. case series

Yes

Probably clinical diagnosis Inclusion– and MRI for some exclusion criteria consecutive series pt stated Low risk of bias

Yes

clinical diagnosis

Low risk of bias

Low risk of bias

Yes

clinical diagnosis

Low risk of bias

Low risk of bias

Low risk of bias

Yes

clinical diagnosis and US

Probably Inclusion– exclusion criteria consecutive series stated

Low risk of bias

Low risk of bias

Low risk of bias

Yes

clinical diagnosis and US

Low risk of bias

Low risk of bias

Prospective case series

Attrition bias

Report. bias

Statist. analysis

none

No withdrawals

Outcome coherently described

p

Low risk of bias

Low risk of bias

No withdrawals

Outcome coherently described

Low risk of bias

Low risk of bias

No per protocol analysis

Outcome coherently described

Low risk of bias

Low risk of bias

No withdrawals

Outcome coherently described

Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

Prospective case series

Recall bias

Low risk of bias Low risk of bias none Probably clinical diagnosis, Inclusion– X-ray and US exclusion criteria consecutive series not stated Unclear risk of bias

Low risk of bias Low risk of bias Not specified if None Inclusion– exclusion criteria consecutive series not stated Unclear risk of bias

High risk of bias

Low risk of bias Not specified if None Inclusion– exclusion criteria consecutive series stated High risk of bias

Low risk of bias

High risk of bias

Select. bias

Yes

clinical diagnosis and MRI for some pt Low risk of bias

Inclusion– exclusion criteria stated Low risk of bias

Low risk of bias

Low risk of bias

Low risk of bias

Inform. bias

Inclusion– exclusion criteria stated Low risk of bias Low risk of bias

clinical diagnosis and US

Outcome Reasons for withdrawal stated; per protocol analysis (few withdrawals, hence coherently described not relevant)

Reasons for withdrawal not stated; no per Outcome protocol analysis coherently described

Miscl. bias

Yes

Low risk of bias None

Low risk of bias Low risk of bias Not specified if None Inclusion– exclusion criteria consecutive series stated

Appropr. study design

Low risk of bias Fanucci et al. 2004 [28]

Select. bias

Low risk of bias

Study and Study design year Deniz et al. 2015 [43]

Inform. bias

Statist. analysis

Low risk of bias Recall bias

None

None

p

None

Low risk of bias p

Low risk of bias

Attrition bias

Report. bias Statist. analysis

Not specified None if consecutive series High risk of Low bias risk of bias None Probably consecutive series

No withdrawals

Outcome coherently described

Low risk of bias

Low risk of bias

No withdrawals

Outcome coherently described

Low risk of bias

Low risk of bias

Low risk of bias

p

None

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Table 3 (Continued) Study and Study design year

Hughes et al. 2007 [29]

Prospective case series

Appropr. study design

Prospective comparative study

Yes

Prospective case series

Low risk of bias

Study and year

Study design

Surgical treatment Retrospective Akermark case series et al. 2008 (Feb) [19]

Bauer et al. 2015 [36]

Biasca et al. 1999 [35]

Dereymaeker et al. 1996 [21]

Faraj et al. 2010 [37]

Kasparek et al. 2013 [22]

Retrospective case series

Retrospective case series

Retrospective case series

Retrospective case series

Retrospective case series

Lee et al. 2011 Retrospective [12] case series

Pace et al. 2010 [38]

Retrospective case series

Probably consecutive series

Inclusion– exclusion criteria stated Low risk of bias Low risk of bias

Probably consecutive series

Inclusion– exclusion criteria stated Low risk of bias Low risk of bias

Probably consecutive series

Clinical diagnosis and US

Yes

Select. bias

Inclusion– exclusion criteria stated Low risk of bias Low risk of bias

Clinical diagnosis and US

Low risk of bias Markovic et al. 2008 [31]

Inform. bias

Clinical diagnosis and US

Yes

Low risk of bias Makki et al. 2012 [30]

Miscl. bias

Low risk of bias

Low risk of bias

Low risk of bias

Recall bias Low risk of bias None

Low risk of bias

Per protocol analysis (few withdrawals, hence not relevant)

Outcome coherently described

Low risk of bias None

Low risk of bias

Low risk of bias

No withdrawals

Outcome coherently described

Low risk of bias

Low risk of bias

Low risk of bias

Yes

Probably consecutive series Low risk of Low risk of bias bias Inclusion– Not specified Clinical exclusion diagnosis and if criteria stated consecutive MRI for all pt series Low risk of bias Low risk of bias High risk of bias Inclusion– Probably Clinical consecutive diagnosis, X-ray exclusion and MRI for all pt criteria stated series Low risk of bias Low risk of bias Low risk of bias Not specified Clinical Inclusion– diagnosis exclusion if criteria not consecutive series stated Low risk of bias Unclear risk of High risk of bias bias Inclusion– Not specified Clinical diagnosis and X- exclusion if criteria not consecutive ray series stated Low risk of bias Unclear risk of High risk of bias bias Not specified Clinical Inclusion– diagnosis exclusion if criteria stated consecutive series Low risk of bias Low risk of bias High risk of bias Inclusion– Not specified Clinical diagnosis and US exclusion if criteria not consecutive for some pt series stated Low risk of bias Unclear risk of High risk of bias bias Not specified n.s. Inclusion– exclusion if criteria not consecutive series stated

Low risk of bias Yes

Low risk of bias Yes

Low risk of bias Yes

Low risk of bias Yes

Low risk of bias Yes

Low risk of bias Yes

Low risk of bias Yes

Inclusion– exclusion criteria stated Low risk of bias

Reasons for withdrawal stated; per Outcome protocol analysis (few withdrawals, coherently described hence not relevant) Low risk of bias

Miscl. bias

Clinical diagnosis

Report. bias Statist. analysis

Low risk of bias None

Appropr. study design

Inform. bias

Attrition bias

Select. bias

Kolmogorov– Smirnov test, Wilcoxon’s signed rank

Student t test

None

Recall bias

Attrition bias

Report. bias

Statist. analysis

None

Reasons for withdrawal stated Low risk of bias No withdrawal

Outcome coherently described Low risk of bias Outcome coherently described

p, SD

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described Low risk of bias Outcome coherently described

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described

Mann–Whitney

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described

p, SD

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described

Chi quadro

Low risk of bias Probably recall bias

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described

None

Low risk of bias None

p, univariate analysis, logistic regression

Fisher’s exact test

None

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Table 3 (Continued) Study and year

Study design

Park et al. 2013 [39]

Retrospective comparative series

Ruuskanen et. Retrospective al 1994 [13] case series

Vito et al. 2003 [24]

Retrospective case series

Appropr. study design

Miscl. bias

Inform. bias

Low risk of bias Yes

Unclear risk of bias Clinical diagnosis and MRI for all pt Low risk of bias

Unclear risk of bias Inclusion– exclusion criteria stated Low risk of bias

Low risk of bias Yes

n.s.

Low risk of bias Yes

Unclear risk of bias Clinical diagnosis

Low risk of bias

Low risk of bias

Select. bias

High risk of bias Probably consecutive series Low risk of bias Not specified Inclusion– exclusion if criteria stated consecutive series Low risk of bias High risk of bias Inclusion– Not specified exclusion if criteria not consecutive series stated Unclear risk of High risk of bias bias

Recall bias

Attrition bias

Report. bias

Statist. analysis

High risk of bias None

Low risk of bias No withdrawal

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described Low risk of bias Outcome coherently described

Low risk of bias None

Low risk of bias No withdrawal

Low risk of bias Outcome coherently described

Low risk of bias

Low risk of bias

Low risk of bias

Recall bias

Attrition bias

Report. bias

Statist. analysis

No withdrawal

Outcome coherently described Low risk of bias

p, SD

Outcome coherently described Low risk of bias

None

Outcome coherently described Low risk of bias

None

Outcome coherently described Low risk of bias

None

Wilcoxon signed-rank test, Mann–Whitney U test, multivariate linear regression

Fisher’s exact test

None

Study and year

Study design

Appropr. study design

Miscl. bias

Akermark et. al. 2008 [44]

Prospective case series

Yes

Clinical diagnosis and Inclusion–exclusion X-ray for some pt criteria stated

Not specified if None consecutive series

Low risk of bias Yes

Low risk of bias

Low risk of bias

High risk of bias

Clinical diagnosis

Inclusion–exclusion criteria not stated

Low risk of bias Yes

Low risk of bias

Unclear risk of bias

Clinical diagnosis

Inclusion–exclusion criteria not stated

Low risk Low risk of bias of bias Reasons for Not specified if None consecutive series withdrawal not stated High risk of bias Low risk Low risk of bias of bias Unknown if Not specified if None consecutive series withdrawal

Low risk of bias Yes

Low risk of bias

Unclear risk of bias

High risk of bias

Clinical diagnosis and Inclusion–exclusion X-ray criteria not stated

Not specified if consecutive series

Low risk of bias

Low risk of bias

High risk of bias

Barrett et al. 1994 [20]

Nashi et al. 1997 [23]

Prospective case series

Prospective case series

Valente et al. 2008 [40]

Prospective case series

Study and year

Study Appropr. design study design

Miscl. bias Inform. bias

Akermark et al. 2013 [45]

RCT

Yes

clinical diagnosis, X-ray and MRI for all pt

Inclusion– exclusion criteria stated

RCT

Low risk of bias Yes

Low risk of bias n.s.

Low risk of bias Inclusion– exclusion criteria stated

Low risk of bias

Unclear Low risk risk of bias of bias

Colgrove et al. 2000 [14]

Inform. bias

Unclear risk of bias

Select. bias

Low risk Unclear risk of of bias bias No withdrawal None

Low risk Low risk of bias of bias

Select. bias

Perform. bias

Detect. bias

Attrition bias

Report. bias

Statist. analysis

Randomiza-tion method explained; number of participant in each block n.s.; concealment of allocation list n.s. Low risk of bias

No blinding of patients/ personnel, except for outcome assessor

Blinding of outcome assessors

Reasons for withdrawal Outcome coherently stated; no per protocol described analysis (except pt satisfaction); pt switched from a group to the other not included in final count

Low risk of bias Randomization No method blinding of explained; patients/ number of personnel, participant in each except for block n.s.; outcome assessor concealment of allocation list n.s. Low risk of Low risk of bias bias

Low risk of bias Blinding of outcome assessors

Unclear risk of bias

Low risk of bias No per protocol analysis Outcome Wilcoxon Rank Sum coherently described

Low risk of bias

Low risk of bias

p, SD, Mann–Whitney U test, chi-square test, Fisher’s exact test, sign test for ordered categorical data and the McNemar test for nominal data

Low risk of bias

Appropr.: appropriate; detect.: detection; diagn.: diagnosis; inform.: information; miscl.: misclassification; n.s.: not stated; perform.: performance; report.: reporting; retrosp.: retrospective; select.: selection; statist.: statistical.

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randomised controlled trials. Their inclusion criteria do not contain a time limit for follow-up. We chose a length of at least 6 months, which is a limit but is still useful. This choice allowed us to compare the three types of treatment and, although the possible appearance of amputation neuromas after one year make it short, all the studies on surgical treatment we included, except one, have follow-ups well above one year. This allowed us not to underestimate this complication. The Cochrane review evaluates three studies, each dealing with a different type of treatment: transposition and resection; supinatory and pronatory insoles; neurectomy through dorsal and plantar incision. The authors admit how difficult it is to draw conclusions and deem the evidence as insufficient for evaluating the effectiveness of surgical versus non-surgical treatments and highlight that controlled randomised studies are necessary for this purpose. We would add that it is vital to standardise outcome measures, which are too varied at present. 4.2. Limitations of the studies The studies about the MNs treatment share similar limitations related to the risk of an overestimation of the results. The clinical outcome is not described by using a standardized system, but it is often defined with an empirical scale, instead of the American Orthopaedics Foot and Ankle Society score (AOFAS) or the Johnson scale. Most of the available studies about MN are case series, for which the researchers do not have the obligation to reduce the selection bias. The inclusion and exclusion criteria, as well as the diagnostic methods, are not always mentioned; consequently, the population at study can potentially comprise not only patients with Morton, but also patients with other types of metatarsalgia, and this cannot be traced unless mentioned by the authors. Since a wrong diagnosis, which could account for the treatment failure, is often not mentioned by authors we decided not to exclude studies in which very few patients (less than five), compared to the total sample, proved to be affected by a non-Morton metatarsalgia. Our systematic review has its main limitation in the inclusion of only one paper about conservative therapy responding to our inclusion and exclusion criteria. This is due to the paucity of such studies, which tend to have a follow-up of one month. A weighted average was performed in order to reduce the influence of the sample size of every study on the results of the review. Nevertheless, the results of our systematic review may have been influenced by the number of the included studies. 5. Conclusions This systematic review suggests that operative treatment leads to better results, followed by infiltrative treatment. The effectiveness of conservative treatments seems less but the paucity of adequate studies makes it hard to assess. It is important to evaluate the risk/benefit ratio through an appropriate reporting of complications and failures for every treatment, in order to decide if it is more suitable to begin treatment with surgery or if it’s better to follow therapeutic algorithms and begin with conservative and infiltrative treatment. Patients should be involved in the choice and physicians should explain clearly the risk/benefit ratio for every treatment. Further studies with high level of evidence, preferably RCTs, are needed. It is also recommended that, in future, researches focus their attentions on identifying the risk and prognosis factors, in order to make the choice of the therapeutical approach less empirical.

Conflict of interest We confirm that this manuscript has not been published elsewhere and is not under consideration by any other journal. All of the authors agree with submission to Foot and Ankle Surgery. We have no conflict of interest to declare. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements We thank Dr. Daniela Vecchio (University of Genoa) for epidemiological consultation and Dr. Roberto Giovannini (University of Milan- Bicocca) for helping in data collection and analysis. References [1] Wu KK. Morton’s interdigital neuroma: a clinical review of its etiology, treatment, and results. J Foot Ankle Surg 1996;35(2)112–9 discussion 187-8. [2] Jain S, Mannan K. The diagnosis and management of Morton’s neuroma: a literature review. Foot Ankle Spec 2013;6(4):307–17, doi:http://dx.doi.org/ 10.1177/1938640013493464. [3] Latinovic R, Gulliford MC, Hughes RAC. Incidence of common compressive neuropathies in primary care. J Neurol Neurosurg Psychiatry 2006;77(2):263– 5, doi:http://dx.doi.org/10.1136/jnnp.2005.066696. [4] Hassouna H, Singh D. Morton’s metatarsalgia: pathogenesis, aetiology and current management. Acta Orthop Belg 2005;71(6):646–55. [5] Bossley CJ, Cairney PC. The intermetatarsophalangeal bursa—its significance in Morton’s metatarsalgia. J Bone Joint Surg Br 1980;62-B(2):184–7. [6] Root ML, Orien WP, Weed JH. Normal and abnormal function of the foot, vol II. Los Angeles, CA: Clinical Biomechanics Corp.; 1977. [7] Gauthier G. Thomas Morton’s disease: a nerve entrapment syndrome. A new surgical technique. Clin Orthop Relat Res 1979;142:90–2. [8] Nissen KI. Plantar digital neuritis; Morton’s metatarsalgia. J Bone Joint Surg Br 1948;30B(1):84–94. [9] Genon MP, Chin TY, Bedi HS, Blackney MC. Radio-frequency ablation for the treatment of Morton’s neuroma. ANZ J Surg 2010;80(9):583–5. [10] Bennett GL, Graham CE, Mauldin DM. Morton’s interdigital neuroma: a comprehensive treatment protocol. Foot Ankle Int 1995;16(12):760–3. [11] Sofka CM, Adler RS, Ciavarra GA, Pavlov H. Ultrasound-guided interdigital neuroma injections: short-term clinical outcomes after a single percutaneous injection—preliminary results. HSS J 2007;3(1):44–9, doi:http://dx.doi.org/ 10.1007/s11420-006-9029-9. [12] Lee KT, Kim JB, Young KW, Park YU, Kim JS, Jegal H. Long-term results of neurectomy in the treatment of Morton’s neuroma: more than 10 years’ follow-up. Foot Ankle Spec 2011;4(6):349–53, doi:http://dx.doi.org/10.1177/ 1938640011428510. [13] Ruuskanen MM, Niinimäki T, Jalovaara P. Results of the surgical treatment of Morton’s neuralgia in 58 operated intermetatarsal spaces followed over 6 (2– 12) years. Arch Orthop Trauma Surg 1994;113(2):78–80. [14] Colgrove RC, Huang EY, Barth AH, Greene MA. Interdigital neuroma: intermuscular neuroma transposition compared with resection. Foot Ankle Int 2000;21(3):206–11. [15] Johnson JE, Johnson KA, Unni KK. Persistent pain after excision of an interdigital neuroma. Results of reoperation. J Bone Joint Surg Am 1988;70 (June (5)):651–7. [16] Hassouna H, Singh D, Taylor H, Johnson S. Ultrasound guided steroid injection in the treatment of interdigital neuralgia. Acta Orthop Belg 2007;73(2):224–9. [17] Thomson CE, Gibson JN, Martin D. Interventions for the treatment of Morton’s neuroma. Cochrane Database Syst Rev 2004;3:CD003118, doi:http://dx.doi. org/10.1002/14651858.CD003118.pub2. [18] Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. Version 5.0.0. The Cochrane Collaboration; 2011. [19] Akermark C, Crone H, Saartok T, Zuber Z. Plantar versus dorsal incision in the treatment of primary intermetatarsal Morton’s neuroma. Foot Ankle Int 2008;29(2):136–41, doi:http://dx.doi.org/10.3113/FAI.2008.0136. [20] Barrett SL, Pignetti TT. Endoscopic decompression for intermetatarsal nerve entrapment—the EDIN technique: preliminary study with cadaveric specimens; early clinical results. J Foot Ankle Surg 1994;33(5):503–8. [21] Dereymaeker G, Schroven I, Steenwerckx A, Stuer P. Results of excision of the interdigital nerve in the treatment of Morton’s metatarsalgia. Acta Orthop Belg 1996;62(1):22–5. [22] Kasparek M, Schneider W. Surgical treatment of Morton’s neuroma: clinical results after open excision. Int Orthop 2013;37(9):1857–61, doi:http://dx.doi. org/10.1007/s00264-013-2002-6. [23] Nashi M, Venkatachalam AK, Muddu BN. Surgery of Morton’s neuroma: dorsal or plantar approach? J R Coll Surg Edinb 1997;42:36–7. [24] Vito GR, Talarico LM. A modified technique for Morton’s neuroma: decompression with relocation. J Am Podiatr Med Assoc 2003;93(3):190–4.

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Please cite this article in press as: S. Valisena, et al., Treatment of Morton’s neuroma: A systematic review, Foot Ankle Surg (2017), http://dx.doi. org/10.1016/j.fas.2017.03.010